Back Clinic Natural Health Functional Medicine Team. This is a natural approach to health care. It is a natural healing practice or a branch of alternative medicine that looks at nature for answers and explanations. There are a few Western forms of alternative medicine that NCCAM has classified as Biologically Based Therapies, as well as, Mind and Body Interventions used in stress management.
There is nothing magical about it. It is about natural healing therapies for prevention and healthy lifestyles. This means eating natural whole foods, nutritional supplements, physical exercise. This is nothing new, but it has evolved over the years within certain prevention parameters, and healthy lifestyles have proven to work repeatedly. There is nothing anti-intellectual or anti-scientific about it. All health, wellness, illness, and healing can be positively affected by simple and inexpensive natural therapies.
Many healthcare professionals highly recommend that patients with multiple sclerosis, or MS, avoid dairy. Several research studies have demonstrated a high correlation between MS and dairy, especially cow�s milk. By way of instance, some of the proteins in cow�s milk are targeted by the immune cells of patients with multiple sclerosis. These include butyrophilin and bovine serum albumin, or BSA. Moreover, injecting those same cow�s milk proteins into test animals caused lesions to appear in their central nervous systems.
Some proteins in cow�s milk imitate part of the myelin oligodendrocyte glycoprotein, or MOG, the section of myelin believed to initiate the autoimmune reaction associated with multiple sclerosis. Furthermore, this can trick the immune system into initiating an attack on the MOG, subsequently causing demyelination. Another research study involving more than 135,000 men and women in the United States determined a connection between cow�s milk and the degenerative neurological disorder, Parkinson�s Disease. Researchers have speculated that dairy products, especially cow’s milk, may have a generally toxic effect on nervous tissue.
Lactose intolerance is common throughout the general population, and it is most notably frequent in Mediterranean, Asian, and African populations. People with lactose intolerance experience a variety of symptoms, including bloating, cramps, diarrhea, and nausea. Given the high potential risks for people with MS consuming dairy products, despite a lack of conclusive evidence, healthcare professionals recommend avoiding the consumption of dairy products, among other types of foods. The purpose of the article below is to discuss the nutrition facts in multiple sclerosis, including which types of foods patients with MS should avoid, such as dairy.
Abstract
The question whether dietary habits and lifestyle have influence on the course of multiple sclerosis (MS) is still a matter of debate, and at present, MS therapy is not associated with any information on diet and lifestyle. Here we show that dietary factors and lifestyle may exacerbate or ameliorate MS symptoms by modulating the inflammatory status of the disease both in relapsing-remitting MS and in primary-progressive MS. This is achieved by controlling both the metabolic and inflammatory pathways in the human cell and the composition of commensal gut microbiota. What increases inflammation are hypercaloric Western-style diets, characterized by high salt, animal fat, red meat, sugar-sweetened drinks, fried food, low fiber, and lack of physical exercise. The persistence of this type of diet upregulates the metabolism of human cells toward biosynthetic pathways including those of proinflammatory molecules and also leads to a dysbiotic gut microbiota, alteration of intestinal immunity, and low-grade systemic inflammation. Conversely, exercise and low-calorie diets based on the assumption of vegetables, fruit, legumes, fish, prebiotics, and probiotics act on nuclear receptors and enzymes that upregulate oxidative metabolism, downregulate the synthesis of proinflammatory molecules, and restore or maintain a healthy symbiotic gut microbiota. Now that we know the molecular mechanisms by which dietary factors and exercise affect the inflammatory status in MS, we can expect that a nutritional intervention with anti-inflammatory food and dietary supplements can alleviate possible side effects of immune-modulatory drugs and the symptoms of chronic fatigue syndrome and thus favor patient wellness.
Keywords:complementary alternative medicine, gut microbiota, inflammation, lifestyle, multiple sclerosis, nutrition
Introduction
Multiple sclerosis (MS) is a chronic, inflammatory, and autoimmune disease of the central nervous system (CNS), leading to widespread focal degradation of the myelin sheath, variable axonal and neuronal injury, and disabilities in young adults, mostly women. The disease is characterized by disseminated and heterogeneous perivascular inflammatory processes at the blood�brain barrier (BBB), with involvement of autoreactive T cells, B lymphocytes, macrophages, and microglial cells against brain and spinal cord white matter (McFarland and Martin, 2007; Constantinescu and Gran, 2010; Kutzelnigg and Lassmann, 2014).
Antibodies (Krumbholz et al., 2012), activated complement (Ingram et al., 2014), cytokines, mitochondrial dysfunction (Su et al., 2009), reactive oxygen species (ROS; Gilgun-Sherki et al., 2004), and matrix metalloproteinases (MMPs; Liuzzi et al., 2002; Rossano et al., 2014) may cooperate to yield the pathology.
From the clinical point of view, there are at least two main forms of the disease: the relapsing-remitting MS (RRMS; about 85% of clinical cases) and the primary-progressive MS (PPMS; about 15% of the clinical cases) (Dutta and Trapp, 2014; Lublin et al., 2014). In RRMS, which usually evolves in secondary-progressive MS (SPMS), relapses are associated with increased systemic inflammation and formation of lesions in the brain, followed by more or less complete remissions, whereas the pathogenesis of PPMS is characterized by progressive neurological damages rather than relapses and remissions.
At present, there are at least 10 disease-modifying therapies that have been found to slow disease progression and prevent some disability symptoms, but only in the case of RRMS. However, as the disease is complex in nature and unique in the individual course, no patient responds to therapy in the same way (Loleit et al., 2014). Similarly, there are no truly reliable biomarkers that allow for everyone to evaluate the effectiveness of treatment and it is therefore important to discover novel markers of the disease (Fernandez et al., 2014).
The lack of response to immune-modulatory therapies in the case of PPMS, otherwise effective in the treatment of RRMS, may be due to different pathogenic mechanisms acting in RRMS and PPMS. However, this is not true with regard to inflammation: A significant association between inflammation and neurodegeneration has been observed in the brain not only in acute and relapsing MS but also in the secondary and primary progressive MS (Frischer et al., 2009; Lassmann, 2013), and active MS lesions are always associated with inflammation (Kutzelnigg and Lassmann, 2014). Thus, inflammation must be the target for the treatment of both forms of the disease.
Linking Inflammation with Dietary Habits and Lifestyle
What causes the inflammatory processes in MS? MS is a complex disease, and the genetic and the immunological components are not sufficient to explain its origin. Actually, MS has a multifactorial nature and various environmental factors or metabolic conditions may have a role in its development (Ascherio, 2013): viral infections (Ascherio et al., 2012; Venkatesan and Johnson, 2014), heavy metal poisoning (Latronico et al., 2013; Zanella and Roberti di Sarsina, 2013), smoking (Jafari and Hintzen, 2011), childhood obesity (Munger, 2013), low vitamin D status (Ascherio et al., 2014), or incorrect lifestyle, including wrong dietary habits (Riccio, 2011; Riccio et al., 2011; Riccio and Rossano, 2013).
None of the above-mentioned environmental factors alone can explain the disease; however, the following considerations make more attractive the involvement in MS of dietary habits and lifestyle, rather than infections or smoking, as factors that may influence the course of the disease:
Geographical distribution: MS is more prevalent in Western countries with the highest income and most distant of the equator. Features of these countries are a sedentary lifestyle, a high-calorie diet rich in saturated fats of animal origin (Western diet), and low sunshine exposure (WHO and MSIF, 2008).
Effect of migration: With the migration from an area of high incidence of MS to another place with low incidence before age of 15 years, the low risk is acquired, while the migration after this age does not change the level of risk. This aspect may be linked with nutritional, rather than with infectious or toxicological environmental factors (McLeod et al., 2011).
Low availability of vitamin D: Another environmental factor related to diet and geographical distribution is the availability of vitamin D, which is lower at latitudes with lower exposure to sunlight. Patients with MS have a low content of vitamin D (Ascherio et al., 2014), but this is true also for other chronic inflammatory diseases (Yin and Agrawal, 2014).
Postprandial inflammation: High animal fat/high sugar and refined carbohydrate diet is associated with postprandial inflammation (Erridge et al., 2007; Ghanim et al., 2009; Margioris, 2009).
High body mass index: High body mass index (BMI) before age 20 is associated with 2� increased risk (Hedstr�m et al., 2012). Note that BMI is correlated with gut microbiota status.
Similarity with other inflammatory diseases related to wrong dietary habits: MS has some similarities with inflammatory bowel disease (IBD; Cantorna, 2012): both have low vitamin D and are influenced from environmental factors (Dam et al., 2013). Furthermore, glatiramer acetate (GA, or Copolymer 1/Copaxone) is beneficial in both diseases (Aharoni, 2013) and there is an increased incidence of IBD among MS patients.
How Food Affects the Course of Inflammatory Diseases: A Basic Approach
The observations reported above suggest that the nutritional status may influence the course of MS. However, the question arises of how dietary molecules could exacerbate or ameliorate MS symptoms, and in general how they could favor or downregulate inflammation at molecular level. In particular, it is important to clarify what are the targets of dietary molecules and the molecular mechanisms involved, if any.
Fundamentally, we can say that the food we consume has a broad impact on our development, behavior, health condition, and lifespan by acting on two main targets: (A) the cells of our body and (B) the commensal gut microbiota (Figure 1).
On one hand, different kind and amount of dietary factors can interact with enzymes, transcription factors, and nuclear receptors of human cells. This may induce specific modifications of cellular metabolism toward either catabolism or anabolism and modulate the inflammatory and autoimmune responses in our body (Desvergne et al., 2006).
On the other hand, we have to consider the impact of diet and lifestyle on our intestinal microflora. We are indeed metaorganisms living with trillions (1014) of microbial cells (roughly 10 times the cells of our body) and thousands of different microorganisms known as the gut microbiota. This complex ecosystem is an essential part of our organism and influences both our immune system and our metabolism. Therefore, it has a strong impact on our health.
In health, there is a close mutualistic and symbiotic relationship between gut microbiota and humans, and gut microbiota provides a number of useful metabolic functions, protects against enteropathogens, and contributes to normal immune functions. This is the normal state of the human intestinal microbiota, called eubiosis. Distortion from eubiosis, linked with a decrease of intestinal biodiversity and increase of pathogenic bacteria, is called dysbiosis. The most common consequence of a dysbiotic gut microbiota is the alteration of the mucosal immune system and the rise of inflammatory, immune, metabolic, or degenerative diseases (Chassaing and Gewirtz, 2014).
Different kinds and amounts of dietary factors elicit the selection of specific gut microbial populations changing type and number of microbial species toward eubiosis or dysbiosis, simply acting through the preferential feeding of one or the other microbial population. If our diet favors the change to a dysbiotic gut microbiota, this may lead to gut inflammation, alteration of intestinal immunity, and then to systemic inflammation and chronic inflammatory diseases.
How Dietary Factors Influence the Metabolism of Human Cells and Modulate Inflammation
To understand how dietary molecules can directly influence the metabolism of human cells, it is necessary to describe first what are the enzymes and transcription factors involved in catabolism or anabolism in the cell.
As shown on the left in Figure 2, oxidative metabolism is upregulated by two enzymes and a nuclear receptor. The enzymes are the AMP-activated protein kinase (AMPK; Steinberg and Kemp, 2009) and the Sirtuins (SIRT), a group of histone deacylating enzymes, which are activated by NAD+ (Zhang et al., 2011; Rice et al., 2012). The nuclear receptor is represented by the isotypes of the peroxisome proliferator-activated receptors (PPARs; Desvergne and Wahli, 1999; Burns and VandenHeuvel, 2007).
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PPAR isotypes upregulate the transcription of genes involved in the beta-oxidation of fatty acids in mitochondria and peroxisomes and form a network with AMPK and Sirtuins pathways. The AMPK-Sirtuins-PPAR pathway is activated by a lifestyle based on calorie restriction and physical exercise, as well as by some bioactive molecules (polyphenols, found in vegetables and fruits, and omega-3 (n-3) long-chain polyunsaturated fatty acids [PUFA], found in fish). Ligand-activated PPAR isotypes form heterodimeric complexes with the retinoid X-receptor (RXR), which, in turn, is activated by 9-cis-retinoic acid (RA).
Conversely, as shown on the right in Figure 2�like on the other dish of an imaginary balance�high intake of energy-dense nutrients leads to the upregulation of anabolism, including lipogenesis and cell growth, through the activation of the sterol regulatory element-binding proteins, SREBP-1c and SREBP-2 (Xu et al., 2013), and the carbohydrate responsive element-binding protein, ChREBP (Xu et al., 2013). SREBP-1c and SREBP-2 are under the control of the nuclear receptors called the liver X receptors (LXR; Mitro et al., 2007; Nelissen et al., 2012). LXR isotypes, which are activated by the cholesterol derivatives oxysterols and glucose, have a relevant role in the synthesis of lipids by activating SREBP-1c and the synthesis of triacylglycerols, while inhibiting SREBP-2 and the synthesis of cholesterol.
Central to the understanding of the link between diet and inflammation are two transcription factors involved in inflammation and autoimmunity: the nuclear transcription factor-kB (NF-kB) and the activator protein (AP-1; Yan and Greer, 2008). In MS, both NF-kB and AP-1 are activated and induce the expression of several proinflammatory genes and the production of proinflammatory molecules. The cause of their activation in MS is not known but, as shown in Figure 2 for NF-kB, this can be activated not only by viruses, cytokines, and oxidative stress but also by some dietary components such as saturated fatty acids or trans unsaturated fatty acids, which therefore can be considered proinflammatory.
Downregulation of the proinflammatory NF-kB can be achieved by the inhibitory binding of the RA-activated forms of the retinoid X-receptor isotypes (RXRs; P�rez et al., 2012; Zhao et al., 2012; Fragoso et al., 2014).
As shown in the center of Figure 2 and more in detail in Figure 3, the active forms of RA-RXRs are heterodimers resulting from their association with specific ligand-activated nuclear receptors, namely PPARs, LXRs, and vitamin D receptor (VDR).
All three nuclear receptors�PPAR, LXR, and VDR�must be activated by specific ligands. As indicated in Figure 2, the ligands can be specific dietary factors and this clarify how cells respond to changes in nutritional status and regulate energy homeostasis but represents also the molecular key to understanding how nutrients can influence the course of chronic inflammatory diseases (Heneka et al., 2007; Zhang-Gandhi and Drew, 2007; Krishnan and Feldman, 2010; Cui et al., 2011; Schnegg and Robbins, 2011; Gray et al., 2012).
Therefore, each of the three nuclear receptors�PPAR, LXR, and VDR�competes for the binding to RA-RXR and forms hetero-complexes that can inhibit NF-kB and exert a tight control over the expression of inflammatory genes, thus integrating metabolic and inflammatory signaling. It is clear that there is competition between the three receptors PPAR, LXR, and VDR-D, for the binding with RA-RXR, but this competition should have an influence only on metabolism and not on inflammation, because it is not yet known which of the three heterodimers is more effective in inhibiting NF-kB.
Obviously, the production of proinflammatory molecules in the course of relapses is a biosynthetic process: It is sustained by hypercaloric diets and counteracted by low-calorie diets. In principle, what favors anabolism will promote the inflammatory processes, while what favors catabolism will contrast them (Figure 4).
How Dietary Factors Influence Composition and Biodiversity of Gut Microbiota and Alter Host�Microbiota Relationship
The Link Between Lifestyle, Dietary Habits, and Gut Microbiota Composition
The composition of the intestinal microflora is highly individual and is influenced by many factors such as diet, physical activity, stress, medications, age, and so forth. Each of us has a unique set of at least 100 to 150 species of bacteria.
An easy way to discuss about the effect of food and lifestyle on gut microflora is to restrict the overview to only two dominant bacterial divisions�the Bacteroidetes and the Firmicutes�accounting for about 90% of the total, as it has been shown that the ratio Bacteroidetes/Firmicutes (B/F) is influenced by long-term dietary habits (Cani and Delzenne, 2009; Wu et al., 2011; Lozupone et al., 2012; Tremaroli and B�ckhed, 2012; Panda et al., 2014).
A comparative study of De Filippo et al. (2010) in children from Florence and from Burkina Faso in Africa showed that long-term dietary habits have significant effects on human gut microbiota.
In this study, the Burkina Faso diet was based on the consumption of plant polysaccharides such as millet and sorghum (10 g fibers/day and 662�992 kcal/day), whereas the diet of Italian children was Western style, based on proteins, animal fat, sugar-sweetened drinks, and refined carbohydrates (5.6 g fibers/day and 1,068�1,512 kcal/day). Analysis of fecal samples in the children from Africa showed the prevalence of the Bacteroidetes (73%)�mainly Prevotella and Xylanibacter�and low levels of Firmicutes (12%). On the contrary, a prevalence of Firmicutes (51%) over the Bacteroidetes (27%) was observed in Italian children, but the Bacteroidetes shifted from Prevotella and Xylanibacter to Bacteroides. These latter are usually selected among the Bacteroidetes because they can use also simple sugars in addition to complex glycans, and simple sugars are normal components of Western diets.
In conclusion, the B/F ratio increases in association with a diet rich in complex carbohydrates (nondigestible by our enzymes) because the symbiotic and usually nonharmful Bacteroidetes, such as Prevotella and Xylani bacter, love to have complex glycans to eat. Bacteria consuming complex glycans produce butyrate, which down regulate the activation of proinflammatory NF-kB (Figure 3).
Conversely, Western, energy-dense diets change the gut microbiota profile and increase the population of Firmicutes (including the Mollicutes), more suited to extract and harvest energy, but often pathogenic (Moschen et al., 2012).
The Link Between Dysbiotic Gut Microbiota and Chronic Inflammation
In a dysbiotic gut microbiota, the B/F ratio is low and the possibly pathogenic Firmicutes prevail over Bacteroidetes (Figure 5). The failure of microbial balance and the decrease of biodiversity occurring in dysbiosis lead to the disruption of the complex interplay between the microbiota and its host and contribute to low-grade endotossemia, and chronic intestinal and systemic inflammation. With the onset of systemic inflammation, the risk of chronic inflammatory and immune-mediated diseases increases (Tilg et al., 2009; Brown et al., 2012; Maynard et al., 2012).
Actually, in the presence of a dysbiotic microbiota, gut endotoxin/lipopolysaccharide (LPS) is increased, regulatory T cells (Treg) are defective, and the aryl hydrocarbon receptors and proinflammatory Th17 cells are activated (Cani et al., 2008; Veldhoen et al., 2008).
LPS leads to the dysfunction of the mucosal barrier and affects other tissues when its plasma level increases above 200 pg/ml serum. The increased gut permeability due to the dysbiotic gut microbiota may be exemplified by the passage of IgA and IgG antibodies against gluten and gliadin, also observed in MS patients (Reichelt and Jensen, 2004).
The Link Between Dysbiotic Gut Microbiota and MS
In our previous work, we have proposed that the model linking microbiota alteration�due to Western diet and lifestyle�and the failure of the correct communication between the microbiota and the intestine, leading to low-grade endotoxemia and systemic autoimmune inflammation, might be valid also for the pathogenesis of MS (Fern�ndez et al., 2012; Riccio, 2011). In fact, MS shares with other chronic inflammatory diseases common mechanisms, all probably based on the persistence of low-grade endotoxemia related to wrong lifestyle and dietary habits together with a latent dysbiosis. Moreover, the existence of a gut microbiota-brain axis, which is now more than an emerging concept, suggests that intervention on gut microbiota may be a fruitful strategy for future treatment of complex CNS disorders (Cryan and Dinan, 2012).
The possible direct link between gut microbiota and MS has been shown experimentally by Berer et al. (2011). Using transgenic mice, Berer et al. have shown that gut commensal bacteria can trigger a relapsing-remitting autoimmune disease driven by myelin-specific CD4+ T cells and demyelination, given the availability of MOG�the autoantigen myelin oligodendrocyte glycoprotein. In another study, it was shown that antibiotic treatment directed to alter gut microflora suppresses experimental allergic encephalomyelitis (EAE; Yokote et al., 2008).
These findings suggest that gut microbiota may play a crucial role in the starting phase of MS and may also predispose host susceptibility to other CNS autoimmune diseases as well as to neuropsychiatric disorders such as autism, depression, anxiety, and stress. A new concept of gut microbiota-brain axis is emerging (Wang and Kasper, 2014).
On these grounds, understanding the role of gut microbiota in health and disease can lay the foundation to treat chronic diseases by modifying the composition of gut microbiota through the choice of a correct lifestyle, including dietary habits. Moreover, direct manipulation of the gut microbiota may improve adaptive immune response and reduce inflammatory secretions. For example, because a specific role of intestinal Th17 cells has been suggested in MS immunopathology (Sie et al., 2014), promoting Treg cell differentiation and reducing pathogenic Th17 cells might prevent recurrence of autoimmunity in MS patients (Issazadeh-Navikas et al., 2012).
On these grounds, the discovery that the defect of the Treg/Th17 balance observed in MS models is also present in MS patients, could have important clinical implications, as this defect can be modulated by changes in the microbiota composition, which in turn is modulated by dietary changes (David et al., 2014).
Proinflammatory Dietary Factors
The components of the diet whose intake must be controlled to avoid the rise of inflammatory processes in MS, as well as in other chronic inflammatory diseases, are as follows:
Saturated fatty acids of animal origin;
Unsaturated fatty acids in the trans configuration (hydrogenated fatty acids);
Red meat;
Sweetened drinks, and in general hypercaloric diets rich in refined (low-fiber) carbohydrates, in addition to animal fat;
Increased dietary salt intake;
Cow�s milk proteins of the milk fat globule membrane (MFGM proteins).
Fat of Animal Origin
Saturated fatty acids of animal origin, which are found in foods such as whole milk, butter, cheese, meat, and sausages, are the components of the diet taken into account more frequently for their deleterious influence on the course of MS.
In 1950, Swank suggested that the consumption of saturated animal fat is directly correlated with frequency of MS, but a link between restricted intake of animal fat and remission of MS was reported only in 2003 (Swank and Goodwin, 2003). According to Swank and Goodwin, high-fat diets lead to the synthesis of storage lipids and cholesterol and cause a decrease of membrane fluidity and possible obstruction of capillaries, and the onset or increase of inflammation.
Other more recent studies indicate that the action of saturated fat is controlled at the transcriptional level and influence both gene expression, cell metabolism, development, and differentiation of cells. More in general, the assumption of animal fat is often linked to a high-calorie intake, which is on its own a detrimental factor for many chronic inflammatory diseases. Finally, as described later in this article, an excess of saturated animal fat leads to a dysbiotic intestinal microbiota, dysfunction of intestinal immunity, and low-grade systemic inflammation and represents a possible cause of some human chronic disorders.
Trans Fatty Acids
Trans fatty acids (TFAs) are unsaturated fatty acids that contain at least one nonconjugated double bond in the trans configuration (Bhardwaj et al., 2011).
As products of partial hydrogenation of vegetable oils, they were introduced in the 1960s to replace animal fat, but only much later it was found that they have the same deleterious effect on the metabolism and, as the saturated fatty acids, increase the levels of cholesterol and promote the formation of abdominal fat and weight gain. TFAs intake was found to be positively associated with gut inflammation and the upregulation of proinflammatory citokines in Th17 cell polarization (Okada et al., 2013). Moreover, TFAs interfere with the metabolism of natural unsaturated fatty acids, which have the cis configuration.
TFAs are found in margarine and other treated (hydrogenated) vegetal fat, in meat and dietary products from ruminants and in snacks. They may be present also in French fries and other fried food, as they are also formed in the frying.
Red Meat
Red meat contains more iron heme than white meat. The iron is easily nitrosylated and this facilitates the formation of endogenous nitroso-compounds (NOCs; Joosen et al., 2010). Red meat intake shows indeed a dose�response relation with NOCs formation, whereas there is no such relation for white meat. NOCs are mutagenic: induce nitrosylation and DNA damage. Processed (nitrite-preserved) red meat increases the risk. Heterocyclic amines are formed during cooking of meat at high temperatures, but this is not specific for red meat (Joosen et al., 2010).
Abnormal iron deposits have been found at the sites of inflammation in MS (Williams et al., 2012) and consumption of red meat is associated with higher levels of ?-GT and hs-CRP (Montonen et al., 2013).
Noteworthy, we do not have N-glycolylneuraminic acid (Neu5Gc), a major sialic acid, because an inactivating mutation in the CMAH gene eliminated its expression in humans. Metabolic incorporation of Neu5Gc from dietary sources�particularly red meat and milk products�can create problems, as humans have circulating anti-Neu5Gc antibodies and this implies the possible association with chronic inflammation (Padler-Karavani et al., 2008).
Finally, meat contains arachidonic acid (the omega-6 (n-6) PUFA, which is the precursor of proinflammatory eicosanoids [prostaglandins, thromboxanes, and leukotrienes]) and activates the Th17 pathway (Stenson, 2014).
High Intake of Sugar and Low Intake of Fiber
The high intake of sugar-sweetened beverages and refined cereals, with low fiber content, increases rapidly the number of calories and glucose level. The subsequent increase of insulin production upregulates the biosynthetic pathways and inter alia the production of arachidonic acid and its proinflammatory derivatives.
Increased Dietary Salt Intake
Increased dietary salt intake might be an environmental risk factor for the development of autoimmune diseases, as it has been found that it can induce pathogenic Th17 cells and related proinflammatory cytokines in EAE (Kleinewietfeld et al., 2013; Wu et al., 2013). Th17 cells have been involved in the development of MS.
Cow�s Milk Fat and the Proteins of the Milk Fat Globule Membrane
Milk fat is dispersed in a homogeneous way and protected from oxidation, thanks to a membrane made of lipids and particular proteins called proteins of the milk fat globule membrane (MFGM; Riccio, 2004). These proteins, which account for only 1% of milk proteins, have an informational rather than a nutritional value. In human lactation, they are needed for the correct formation of the digestive, nervous, and immune systems in infants. This flow of information is obviously not relevant, or not required at all, in adulthood and, as well, in the case of cow�s milk taken for human nutrition. In adult age, MFGM proteins of cow�s milk no longer have an informational role and may be eliminated from the diet together with milk fat.
The removal of MFGM proteins from whole cow�s milk is particularly relevant in the case of MS. The most representative MFGM protein (40% of total MFGM proteins), butyrophilin (BTN), is indeed suspected to have a role in MS, as it is very similar to MOG, one of the candidate autoantigen in MS. BTN and MOG share the same behavior in MS experimental models, and MOG/BTN cross-reactive antibodies have been found in MS, in autism and in coronary heart disease (CHD; Riccio, 2004). On these grounds, the patient with MS should avoid the intake of whole cow�s milk and prefer skimmed milk, which, in addition, has no animal fat.
Another point of view is that of Swanson et al. (2013). They have found that BTN or BTN-like molecules might have a regulatory role in immunity and therefore they suggest that BTN or BTN-like molecules could be useful to induce Treg development.
Hypercaloric Diets and Postprandial Inflammation
After each meal, we may experience a transient and moderate oxidative stress and a moderate inflammatory response depending on type and quantity of food. Dietary habits based on a frequent and persistent exposure to meals with high intake of salt/animal fat and trans fat/sugar-sweetened drinks stresses our immune/metabolic system and the subsequent possible failure of homeostasis may lead to immune and metabolic disorders of diverse nature.
Taken together, the diet-dependent stress might be due to following reasons: (a) calorie intake: the higher the calories, the more the oxidative stress induced; (b) glycemic load of a meal: acute postprandial glycemic peaks may induce a release of insulin much higher than necessary; (c) lipid pattern: saturated animal fat, trans fatty acids, and omega-6 (n-6) long-chain PUFA promote postprandial inflammation. As reported in the following sections, postprandial inflammation is attenuated or suppressed by n-3 PUFA and polyphenols, calorie restriction, and physical exercise.
Anti-Inflammatory Natural Bioactive Compounds: Useful to Tackle MS and Prevent Relapses?
Specific bioactive dietary molecules are able to counteract the effects of pathogenic microbial agents and downregulate the expression of inflammatory molecules. Among them, the most important compounds are the polyphenols and carotenoids from vegetables, n-3 PUFA from fish, vitamins D and A, thiol compounds such as lipoic acid, and oligoelements such as selenium and magnesium.
Most of the above-mentioned compounds, with exception of PUFA, which are not antioxidant, are known for their antioxidant properties. The rationale for the use of antioxidants in MS is based on the observation that oxidative stress is one of the most important components of the inflammatory process leading to degradation of myelin and axonal damage. However, it is now known that dietary antioxidants have additional biological properties going far beyond the simple antioxidant activity. Indeed, they are able to counteract the negative effects of microbial agents and saturated or trans fatty acids, downregulating the expression of proinflammatory molecules, oxidative stress, and angiogenesis.
Polyphenols
All polyphenols�which are present in vegetables, cereals, legumes, spices, herbs, fruits, wine, fruit juices, tea, and coffee�have anti-inflammatory, immune-modulatory, anti-angiogenic, and antiviral properties and stimulate the catabolic pathways (Gupta et al., 2014; Wang et al., 2014). They are found in plants in the form of glycosides, esters, or polymers, too large to enter the intestinal membrane. Aglycons released from gut microbiota are conjugated to glucuronides and sulfates in intestine and liver. Their solubility and bioavailability are very poor (�M; Visioli et al., 2011).
From a structural point of view, polyphenols include flavonoids and nonflavonoids molecules (Bravo, 1998). The most important flavonoids are quercetin (onions, apples, citrus fruit, and wine; Min et al., 2007; Sternberg et al., 2008), catechins (green tea; Friedman, 2007), and daidzein and genistein (soy; Castro et al., 2013; Zhou et al., 2014). The most important nonflavonoids are resveratrol (chocolate, peanuts, berries, black grapes, and red wine; Das and Das, 2007; Cheng et al., 2009; Shakibaei et al., 2009), curcumin (spice turmeric of ginger family, curry; Prasad et al., 2014), and hydroxytyrosol (olive oil; Hu et al., 2014).
It has been found that the anti-inflammatory effect of polyphenols in vitro may depend on their chemical structure (Liuzzi et al., 2011). Thus, a mixture of flavonoids and nonflavonoids may be more effective than supplementation with only one polyphenol.
Two examples of the most studied polyphenols are quercetin and resveratrol. Quercetin is present mainly as a glucoside. Most of its effects are additive to those of interferon-?. Quercetin is not toxic, but its oxidation product, quercetin quinone, is very reactive toward the SH groups of proteins and glutathione and may be toxic (Boots et al., 2008). Addition of lipoic acid or N-acetylcysteine can limit the toxic effects.
Resveratrol is glucuronated in the liver and absorbed in this form mainly in the duodenum but only in very limited amount. Depending on its concentration, resveratrol can induce the death of a wide variety of cells by necrosis or apoptosis. In this regard, it is commonly accepted that resveratrol has neuroprotective effects; however, it has been also reported that it can exacerbate experimental MS-like diseases (Sato et al., 2013). These discrepancies can be attributed to the different concentrations used in vitro or bioavailable in vivo, as resveratrol has opposite effects at concentrations of 10?5 M (proliferation of human mesenchimal cells) and 10?4 M (inhibition of proliferation). In our experience, resveratrol has a neurotrophic effect on cortical neurons in culture only at very low concentration, whereas at higher concentration, it may have toxic effect. But in the case of oxidative stress, resveratrol has neuroprotective properties also at the higher concentrations.
Vitamin D, Vitamin A, Carotenoids, Other Vitamins, and Oligoelements
Other compounds and elements that may be useful as supplements in MS are the vitamins D, A, E, C, B12 (Mastronardi et al., 2004), and niacin (Penberthy and Tsunoda, 2009), and oligoelements such as selenium (Boosalis, 2008) and magnesium (Galland, 2010).
Vitamin D has immune-modulatory roles and represents the most promising dietary molecule for the treatment of chronic inflammatory diseases such as MS (Smolders et al., 2008; Pierrot-Deseilligny, 2009; Cantorna, 2012; Ascherio et al., 2014). As already mentioned, it is generally believed that the special geographical distribution of MS in the world can also be attributed to the reduced availability of vitamin D3, due to insufficient exposure to sunlight in some countries, and the lack of active vitamin D may be another possible cause of environmental origin of MS. However, low levels of active vitamin D may be due also to its altered metabolism or function not only to the exposure to sunlight. In fact, the failure of vitamin D3 (cholecalciferol) supplementation to show beneficial effects on body weight or on the course of inflammatory diseases may be due to the persistence of its deficiency despite its administration.
Vitamin D3 (cholecalciferol), formed after exposure to sunshine, is hydroxylated in the liver to 25-(OH) D3 (calcidiol) by the P450 enzymes CYP27A1 or CYP2R1, and subsequently activated in the kidney by CYP27B1 to 1?, 25-(OH)2 D3 (calcitriol). This latter, the active form of vitamin D, is inactivated by CYP24A1 to 1?, 24,25-(OH)3 D3 (calcitroic acid). This means that the levels of active vitamin D depend on the relative rates of its synthesis via CYP27B1 and its modifications via CYP24A1 (Schuster, 2011). High CYP24A1 expression, induced by endogenous compounds and xenobiotics, might lead to low levels of vitamin D and cause or enhance chronic inflammatory diseases and cancer. On these grounds, it is important to follow up the level of vitamin D in the course of vitamin D administration. If vitamin D levels remain low, the expression of CYP24A1 mRNA should be examined, and determination of CYP27B1 and CYP24A1 activities and their inhibition should be tested (Chiellini et al., 2012, K�sa et al., 2013).
Another important aspect regards the VDR. The active metabolite of vitamin D�1?, 25-dihydroxyvitamin D�binds to VDR, and the complex VDR-D controls the expression of several genes involved in processes of potential relevance to chronic diseases. As represented in Figures 2 and and3,3, the VDR-D complex competes with ligand-activated PPARs or LXRs for the binding to RA-RXR. The heterodimeric complexes bind to the proinflammatory transcription factor NFkB and downregulate the synthesis of proinflammatory molecules. In this context, when evaluating the effectiveness of vitamin D supplementation in the course of MS, one should consider the eventual polymorphisms affecting the VDR, which has been recently associated with obesity, inflammation, and alterations of gut permeability (Al-Daghri et al., 2014).
Moreover, the finding that that VDR-D activate the Sirtuin SIRT-1 (An et al., 2010; Polidoro et al., 2013) suggests that vitamin D has an influence also on cell metabolism and therefore may have properties similar to those of many other natural dietary supplements: upregulate oxidative metabolism and downregulate inflammation.
Finally, it should be considered that there are differences between data in humans and experimental models. Actually, in humans, unlike in mice, obesity is associated with poor vitamin D status (Bouillon et al., 2014).
Among the carotenoids, the most important is lycopene (tomato, water melon, and pink grape fruit; Rao and Rao, 2007). Besides to be a very strong antioxidant, lycopene can give beta-carotene and retinoic acid, and the latter can activate the RXR receptor (Figure 2). Although higher intakes of dietary carotenoids, vitamin C, and vitamin E did not reduce the risk of MS in women (Zhang et al., 2001), the relevance of lycopene and vitamin A against inflammation cannot be disregarded.
Omega-3 (n-3) Essential Fatty Acids and Poly-Unsaturated Fatty Acids from Vegetables, Seafood, and Fish Oil
n-3 essential fatty acids (EFA) and PUFA represent a valid alternative to saturated fatty acids of animal origin.
Vegetable and vegetable oils contain the essential fatty acids linoleic acid (n-6) and linolenic acid (n-3). n-6 and n-3 fatty acids have opposite effects and their presence in the diet should be equivalent (Schmitz and Ecker, 2008). However, in Western diets, the ratio n-6/n-3 is increased from 6 to 15 times and this leads to a higher incidence of cardiovascular and inflammatory diseases. In fact, the linoleic acid leads to the formation of arachidonic acid (20:4), the precursor of the proinflammatory eicosanoids prostaglandins-2, leukotrienes-4, and thromboxanes-2. The synthesis of these eicosanoids is favored by insulin, and inhibited by aspirin, as well as by the n-3 long-chain PUFA EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), which derive from n-3 linolenic acid.
Both DHA and EPA are found in seafood and fish oil. Both show remarkable anti-inflammatory, anti-thrombotic, and immune-modulatory activities, comparable with those of statins (Calder, 2006; Farooqui et al., 2007). n-3 PUFA inhibit inflammatory processes and the synthesis of fatty acids and cholesterol, and instead they stimulate the oxidation of fatty acids. On this basis, in chronic inflammatory diseases such as MS, n-3 essential fatty acids (EFA) and n-3 PUFA should prevail in the diet over the n-6 fatty acids. It is interesting to note that DHA is present in high concentrations in the brain and its levels decrease in patients with MS.
In cultured microglial cells activated by LPS, fish oil is as effective as interferon-? in inhibiting the expression of MMP-9 (gelatinase B), an important mediator of neuro-inflammation (Liuzzi et al., 2004, 2007). Moreover, n-3 PUFA significantly decreased MMP-9 levels in few clinical trials, indicating that n-3 PUFA may represent a good complementary treatment in the course of MS (Weinstock-Guttman et al., 2005; Mehta et al., 2009; Shinto et al., 2009). Fish oil has been also found to improve motor performances in healthy rat pups (Coluccia et al., 2009).
n-3 PUFA act in synergy with aspirin on AMPK and COX enzymes but with different mechanisms. Noteworthy, in the presence of aspirin, EPA and DHA form new anti-inflammatory bioactive molecules called resolvins, protectins, and maresins, which are able to reduce cellular inflammation and inflammatory pain (Xu et al., 2010; Hong and Lu, 2013; Serhan and Chiang, 2013). This may be a relevant aspect related to the nutritional intervention in MS. Indeed, the inflammatory processes associated to MS could be also due to the low ratio omega-3 (anti-inflammatory)/omega 6 (inflammatory) PUFA and thereby to the low production of adequate amounts of resolution-inducing molecules lipoxins, resolvins, and protectins that suppress inflammation. Hence, administration of omega-3 PUFA together with aspirin or directly of lipoxins, resolvins, and protectins may form a new approach in the prevention and treatment of MS and other neuroinflammatory diseases. Furthermore, other anti-inflammatory and antiangiogenic eicosanoids can also be produced by the P450 CYP enzymes from EPA and DHA (Yanai et al., 2014). In this context, it should be taken into consideration that statins may interfere negatively with the metabolism of n-3 and n-6, as they can decrease the n-3/n-6 ratio. Thus, treatment with statins should be associated with n-3 PUFA supplementation (Harris et al., 2004).
Seeds oils, from sunflower, corn, soybean, and sesame, contain more n-6 fatty acids than n-3 fatty acids and therefore their assumption should be limited in MS, in order to limit the level of proinflammatory eicosanoid production. On the other hand, coconut oil has a high content of saturated fatty acids. Among vegetable oils, olive oil should be preferred for the good ratio between saturated and unsaturated fatty acids, and because it contains the antioxidant hydroxytyrosol.
Thiolic compounds as Dietary Supplements
Compounds containing thiol groups (�SH) such as ?-lipoic acid (ALA), glutathione, and N-acetylcysteine (NAC) should be taken into consideration as possible dietary supplements to be used for the complementary treatment of MS.
As polyphenols, ALA (Salinthone et al., 2008; green plants and animal foods) has immunomodulatory and anti-inflammatory properties. ALA stabilizes the integrity of the BBB and stimulates the production of cAMP and the activity of protein kinase A. Also NAC might be useful in neurological disorders. It passes through the BBB and protects from inflammation (Bavarsad Shahripour et al., 2014).
The Mediterranean Diet
A recent systematic review and meta-analysis of intervention trials provide evidence that Mediterranean diet patterns reduce inflammation and cardiovascular mortality risk and improves endothelial functions (Schwingshackl and Hoffmann, 2014). These findings are as much encouraging as you think that the true Mediterranean diet is a little different from the one currently described.
It is generally agreed that the Mediterranean diet is based on consumption of extra-virgin olive oil, unrefined cereals, legumes, diverse vegetables (in particular tomatoes) and fruits, dairy products (mostly as pecorino cheese, ricotta, mozzarella, and yogurt), fish and fishery products, and low consumption of animal fat and meat. However, currently, the Mediterranean diet tends to a high consumption of pasta and bread, which means a high intake of gluten.
Once, in true Mediterranean diet, in Southern Italy, meat was eaten two or at most three times a week, only olive oil was used for cooking (extra-virgin quality and the most possible raw), but notably the intake of gluten was about half compared with the current intake. The pasta was eaten with the classic home-made tomato sauce, but in alternative, it was most often mixed with other gluten-free foods. The most common recipes were pasta and potatoes; pasta with either green beans, or artichokes, zucchini, eggplant, turnips, or cabbage; pasta with a mix of vegetables and legumes (minestrone: vegetable soup); and pasta with chickpeas, beans, or lentils. The sugar-sweetened drinks of today were not known. A high assumption of gluten-rich food may lead to nonceliac asymptomatic gluten sensitivity, mucosal intestinal damage, changes in gut microbiota, and low-grade intestinal inflammation. In conclusion, the Mediterranean diet is good, but the intake of gluten must be limited and must be whole grains.
Inflammatory and Anti-Inflammatory Lifestyle
Smoking (Proinflammatory)
Only a few studies have been carried out on the impact of smoking on the course of MS and results are conflicting, perhaps because its effects are difficult to ascertain and enucleate from other factors. Weiland et al. (2014) have found no association between smoking and relapse rate or disease activity, but do not exclude that smokers might have a significantly lower health-related quality of life than non-smokers, whereas Manouchehrinia et al. (2013) found that smoking is associated with more severe disease.
However, as it is shown in Figure 2, it can be expected that cigarette smoke may worsen the course of MS, as it may inhibit the anti-inflammatory activity of Sirtuins (Caito et al., 2010). The oxidative and carbonyl stress induced by cigarette smoke can be reversed by resveratrol (Liu et al., 2014).
Alcohol Consumption (Proinflammatory)
Recent studies shows that alcohol (beer, wine, or liquor) consumption is not associated to MS risk (Massa et al., 2013; Hedstr�m et al., 2014). However, as also shown in Figure 2, alcohol may inhibit the Sirtuin SIRT1 and activate the transcriptional activity of SREBP-1c (You et al., 2008), thus promoting the biosynthesis of lipids and inflammation at the expense of oxidative metabolism.
There are other two aspects of ethanol that should be considered. First, the metabolism of ethanol converts a large number of NAD+ molecules to NADH, limiting the availability of NAD+ required for the activity of Sirtuins. Second, as a substrate of the P450 enzymes, ethanol can interfere with the metabolism of drugs, which are transformed by the same enzymes. The result may be the prolongation and the enhancement of drug action. Altogether, alcohol should be considered as a molecule that interferes with the normal metabolism and facilitates the inflammatory process, complicating the possibility of improving the wellbeing of the patient.
Calorie Restriction (Anti-Inflammatory)
High-calorie intake and a meal rich in refined carbohydrates and sugar increase insulin level and favors biosynthesis, including the production of proinflammatory molecules and the production of free radicals. Calorie restriction, obtained by decreasing food intake or by intermittent fasting (one day and the other not), upregulates the level of SIRT1 (Zhang et al., 2011), increases the level of AMP and upregulates AMPK, increases adiponectin levels and upregulate or activate its receptors (Lee and Kwak, 2014), and downregulates oxidative damage, lymphocyte activation, and the progression of experimental models of MS (Piccio et al., 2008, 2013). The effects of calorie restriction can be mimicked by agonists (resveratrol and other polyphenols), acting on the same targets (SIRT1, AMPK).
Physical Exercise (Anti-Inflammatory)
Physical exercise is now an almost accepted practice also for MS patients and is commonly applied in order to decrease the symptoms of chronic fatigue and prevent or slow the onset of disability. However, the importance of physical exercise goes beyond that of simple muscle activity and should be rather considered in a holistic context in which diet, exercise, therapy, and social interchange, all play a role for the wellness of MS patients (Gacias and Casaccia, 2013).
Dietary control and exercise practice have been proposed by the WHO (2010) to attenuate or prevent human chronic diseases.
From a molecular point of view, physical exercise exerts its beneficial effect by acting on the protein kinase AMPK axis and the AMPK�Sirtuins�PPAR-? network, upregulating oxidative metabolism and downregulating biosynthetic pathways and inflammation (Narkar et al., 2008). As AMPK has a key role in energy balance, it is important to mention its agonists. Resveratrol and AMPK agonists such as metformin, a drug used in type 2 diabetes, can mimic or enhance the effect of physical activity and are effective in experimental encephalitis (Nath et al., 2009).
Physical exercise influences the quality of life and may stimulate the production of anti-inflammatory cytokines (Florindo, 2014). Furthermore, physical exercise lowers plasma levels of leptin and reduces gene expression of leptin receptors in the liver (Yasari et al., 2009), while increasing adiponectin levels and adiponectin receptors activity (Lee and Kwak, 2014).
The association of physical exercise with calorie restriction leads to a significant reduction of inflammatory markers (Reed et al., 2010).
Recent studies carried on adult C57BL/6 J male mice have shown that exercise stimulate brain mitochondrial activity, potentiate neuroplasticity, and is associated to mood improvement, as it decrease anxiety-like behaviors in the open field and exert antidepressant-like effects in the tail suspension test (Aguiar et al., 2014). Other studies performed on rats showed that exercise can alter the composition and diversity of gut bacteria (Petriz et al., 2014).
On these grounds, MS patients should practice mild physical exercise (brisk walking, swimming, or even dancing), if possible in the course of a rehabilitation program.
Nutritional Clinical Trials in MS So Far
Unfortunately, nutritional clinical trials in MS are only very few. Some of them were based on diets low in saturated fat, either without supplements (Swank and Goodwin, 2003) or with omega-3 fat supplements (Nordvik et al., 2000; Weinstock-Guttman et al., 2005). Other clinical trials were based on the administration of single dietary supplements only: either vitamin D, or fish oil (n-3 PUFA), or lipoic acid. Clinical trials with single polyphenols were performed only in cancer. Dietary supplements have never been used together and have never been associated with dietary prescription.
Taken together, clinical attempts to clarify the role of nutrition in MS were considered only promising of poor quality or with no clear results (Farinotti et al., 2007, 2012). In particular, as reported by Farinotti et al. in their Cochrane review (2012), supplements such as n-3 PUFA seem to have no major effect on the main clinical outcome in MS, but they may reduce the frequency of relapses over 2 years. Data available were considered to be insufficient or of uncertain quality to assess a real effect from PUFA supplementation. In some studies, slight possible benefits in relapse outcomes were found with omega-6 fatty acids, but data were characterized by the reduced validity of the endpoints. In general, trial quality was found to be poor. Studies on vitamin supplementation were not analyzed as none met the eligibility criteria, mainly due to lack of clinical outcomes. Thus, evidence on the benefits and risks of vitamin supplementation and antioxidant supplements in MS is lacking.
Suggestions for a Nutritional Intervention in MS: The Choice of Diet and Dietary Supplements
At the end, the goal of a nutritional intervention in MS must be the control of inflammation and this, as shown in this review, can be achieved mainly by controlling postprandial inflammation, the composition of gut microbiota and intestinal and systemic inflammation, and immunity. This can be achieved by a long-term dietary intervention, with a hypocaloric diet, prebiotics, probiotics, and dietary supplements.
As reported in this article, healthy dietary molecules, calorie restriction, and exercise are able to direct cell metabolism toward catabolism and downregulate anabolism and inflammation by interacting at different levels with specific enzymes, nuclear receptors, and transcriptional factors. Furthermore, in association with fiber, they can shift gut dysbiosis to eubiosis.
As a result, low-calorie meals (1,600�1,800 kcal) based on vegetables, whole cereals, legumes, fruit, and fish may slow down the progression of the disease and ameliorate the wellness of MS patients, whereas hypercaloric diets with high intake of salt, saturated animal fat, fried food, and sugar-sweetened drinks may lead to the onset of postprandial inflammation and systemic low-grade inflammation.
Diet should be integrated with prebiotics, probiotics, specific vitamins (D, A, B12, and nicotinic acid), oligoelements (magnesium and selenium), and dietary supplements such as polyphenols, n-3 PUFA, and lipoic acid.
Prebiotics for MS should include inulin, bran, lactosucrose, and oligofructose, preferential nutrients for colonocytes and capable to inactivate NF-kB. Probiotics, such as lactococcus lactis, bifidobacterium lactis, and clostridium butyricum, which can improve the intestinal microbial balance, can be used to change the composition of colonic microbiota. The combination of prebiotics and probiotics is highly recommended. Bowel functions and weight should always be under control.
A more drastic therapeutic approach aimed to restore gut eubiosis and downregulate inflammation may be represented by fecal microbiota transplantation (FMT; Smits et al., 2013). The method seems to be very effective but still primitive, not completely safe, and in a way also disgusting. The field should move beyond fecal transplants, identify the organisms that may be essential for a particular condition, and provide those organisms in a much simpler fashion than FMT (�Critical Views in Gastroenterology & Hepatology,� 2014).
Dietary supplements, with the only exception of omega-3 PUFA, which are normal constituents of our body, are useful at the beginning of the nutritional intervention, or in the course of relapses, to facilitate the recovery of a healthy condition, but their use should be restricted to only a limited period of time (3�4 months). This is particularly valid for the polyphenols. Polyphenols are not well-known molecules with regard to their bioavailability and their biological effects and special precautions should be used when supplementing the diet with them. On one hand, they can downregulate the synthesis of proinflammatory molecules in the course of inflammatory processes; on the other hand, they can stimulate cell activity in resting cells, but a persistent stimulation can induce the apoptosis of healthy cells. Taken together, these considerations suggest that administration of purified polyphenols should be performed on the basis of preliminary clinical trials to test their effectiveness as dietary supplements and to determine their long-term safety and the right dosage.
In general, a nutritional intervention with anti-inflammatory food and dietary supplements decreases the biosynthesis of proinflammatory compounds and therewith makes more effective the use of immune-modulatory drugs, and eventually might limit their possible adverse effects, alleviate the symptoms of chronic fatigue syndrome, and favor patient wellness. However, diet and dietary supplements should not be treated as drugs and as a substitute of therapy. Similarly, proinflammatory food is not toxic and there is no need to exclude it completely. You can eat a nice steak or fried food without risk or guilt, if you are in a basically healthy condition. What hurts are the wrong eating habits in the long run.
Multiple sclerosis, or MS, is a chronic, progressive disease involving damage to the myelin sheaths of nerve cells. The epidemiology of MS suggests that various factors are often involved in the clinical expression of the health issue. However, numerous research studies have primarily evaluated the role of diet on the development of multiple sclerosis. For several years, healthcare professionals believed there was a correlation between the consumption of dairy in patients with multiple sclerosis. According to various research studies, a significant correlation between cow milk and the prevalence of multiple sclerosis was found, suggesting a possible role of dairy products in the multifactorial etiology of MS. Dr. Alex Jimenez D.C., C.C.S.T.
Conclusions
So, at first glance, MS does not seem to have any of the characteristics of chronic inflammatory diseases, which could be related to wrong dietary habits and lifestyle, or even to a dysbiotic gut microbiota. There is apparently nothing in an exacerbation of the disease that may be linked to food or the state of the intestinal microbiota. In fact, when we began our studies on the impact of nutrition on MS, there was not even the slightest clue that there could exist a real link between them, and the idea of the involvement of gut microbiota in MS was considered only very speculative. To date, the idea that dietary habits might influence the course of MS is still struggling to establish itself. Not so in cardiovascular diseases and other chronic inflammatory conditions, in which the influence of dietary habits is almost accepted, and not even in cancer, which is increasingly considered as a metabolic disorder (Seyfried et al., 2014).
At present, MS therapy is not associated to any particular diet, probably due to lack of information on the effects of nutrition on the disease. However, the majority of patients with MS is looking for complementary and alternative treatments (CAM), and in particular is trying to change dietary habits, almost without the advice of the physician (Schwarz et al., 2008; Leong et al., 2009). A recent study based on data provided by MS patients in response to a questionnaire on their dietary habits seems to support a significant association of healthy dietary habits with better physical and mental health-related quality of life and a lower level of disability (Hadgkiss et al., 2014). These data reinforce the idea of the need for randomized controlled trials of nutritional intervention for people with MS. It should be emphasized that nutritional treatments should be complementary, but not alternative to therapy, be part of a holistic approach and performed under medical control.
As there are no data available from clinical trials yet, our work is aimed to rationalize dietary choices on the basis of known and established effects of dietary factors and lifestyle at the molecular level. Data reported in Figure 2 are obviously not complete but may be useful to provide guidelines for nutritional interventions. In principle, proinflammatory food upregulate the biosynthetic and inflammatory pathways, as shown on the right and at the bottom of Figure 2, whereas anti-inflammatory food upregulates oxidative metabolism and downregulates anabolism and inflammation.
As shown in this article, the finding that calorie restriction, exercise, and particular dietary factors can influence the degree of inflammatory responses by acting on both cellular metabolism (Figure 2) and composition of gut microbiota (Figure 5), suggests that an appropriate nutritional intervention may ameliorate the course of the disease and may be therefore taken in consideration as a possible complementary treatment in MS. As inflammation is present in both RRMS and PPMS, nutritional advices are indicated for both forms of the disease. This is particularly important in the case of PPMS, for which no cure is presently available. Conversely, as specific dietary habits may be detrimental and may promote a chronic state of low-grade inflammation, a wrong diet may be considered a possible contributory cause of relapses in MS.
Taken together, we have now a better knowledge of the possible influence of dietary factors on cell metabolism and gut microbiota, and on their possible effects on the disease, but, clearly, we are only just beginning to understand the role of nutrition and gut microbiota in MS and much work remains in terms of understanding the nature of the interactions of gut microbiota with the host�s immune system, especially at sites distal to the intestine.
On these grounds, future prospects in MS research should regard the following points: (a) assess gut microbiota composition; (b) evaluate defects in intestinal immune system; (c) clarify the role of polyphenols and vitamin D metabolism; (d) study the impact of dietary factors, herbs, and drugs on AMPK, Sirtuins, PPAR, or directly on NF-kB. Noteworthy, some drugs used to treat type II diabetes, such as the PPAR-? agonists thiazolidinediones (Bernardo et al., 2009), and the AMPK agonist metformin (Nath et al., 2009) have anti-inflammatory effects comparable with those of anti-inflammatory dietary factors; (e) define possible interferences between dietary supplements and MS drugs; (f) promote a campaign aimed to educate about the importance to follow a healthy diet during therapy, for instance, encouraging patients to include fiber or complex carbohydrates in their diet, supplementing with probiotics, choosing n-3 fats over proinflammatory n-6 fats, and limiting meat and animal fat consumption. The choice of good recipes, such as those described by Mollie Katzen (2013), can make the diet more acceptable.
Overall, immune-modulatory conventional MS therapies have been almost successful; however, drugs that can protect and favor repair mechanisms are still missing. We can decide to help people stay healthy by providing nutritional guidance and physical activity opportunities. For the moment, there are only good prospects for improving the wellbeing of patients with MS. We are only at the beginning of the story.
Summary
As both relapsing-remitting MS and primary-progressive MS are inflammatory diseases, they can be influenced by proinflammatory or anti-inflammatory dietary habits and lifestyle through their action on cell metabolism and gut microbiota. Nutritional advice to MS patients may favor their wellness.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported by the Italian Foundation for Multiple Sclerosis (FISM) with grants 2007/R/15 for the Project �Healthy and Functional Foods for MS patients,� 2010/R/35 for the Project �The Molecular Basis for Nutritional Intervention in Multiple Sclerosis,� and 2014/S/2 (2014�2015) for the project �Nutritional Facts in Multiple Sclerosis: Why They Are Important and How They Should Be Managed� to P. R.
Many doctors greatly recommend that patients with multiple sclerosis, or MS, avoid dairy because various research studies have demonstrated a high correlation between MS and dairy, especially cow�s milk. This is largely due to the fact that the proteins in cow�s milk are generally targeted by the immune system of patients with multiple sclerosis. Furthermore, some proteins in cow�s milk imitate part of the myelin oligodendrocyte glycoprotein, or MOG, the section of myelin which triggers the autoimmune response in multiple sclerosis that can trick the immune system to attack and destroy the MOG. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �
If you are currently thinking about the ketogenic diet, then you might be asking yourself, is the keto diet right for you? While you may have already heard about the benefits of the ketogenic diet, you might still be wondering about whether if it is worth it to completely change your diet to take advantage of these benefits.
The keto diet has many benefits, from weight loss and improved physical health to mental clarity and enhanced physical performance. In the following article, we will dive into the details of some of the ketogenic diet health benefits. These benefits can help with the particular health goal you may be attempting to attain.
Ketogenic Diet and Weight Loss
In comparison to low-fat dieting, a low-carb diet can deliver superior results within a shorter time period in terms of weight loss, and the management of cholesterol, and blood pressure. If you want to shed weight, the ketogenic diet plan provides the following benefits and will get you closer to attaining your objective. There can be many reasons for this, including:
Low-carb and ketogenic diets are more satisfying with their low carb content and higher quantities of fats and protein.
Going onto a low-carb diet usually makes you lose extra water weight.
Most individuals can undergo weight loss fairly quickly, especially within the first week�of beginning a ketogenic diet.
Increased HDL Cholesterol
Together with the high consumption of saturated fats and other healthy fats, the ketogenic diet may help raise HDL cholesterol and enhance triglycerides levels. Both of these are�considerably significant towards promoting heart health.
Ketogenic Diet and Physical Health
Acne
Following the ketogenic diet has been demonstrated to also be able to help reduce inflammation and lesions of the skin like those found in acne. This is believed to occur due to the effects of ketosis, or the state in which the cells use ketones instead of glucose for energy.
IBS Support
Moreover, several research studies have also associated a link between the reduced consumption of glucose, or sugar, and an improvement in symptoms of irritable bowel syndrome, or IBS. As a matter of fact, one research study demonstrated that following a ketogenic diet may improve bowel movement habits and help reduce abdominal pain, improving quality of life in people with IBS.
Ketogenic Diet and Physical Performance
Balanced Energy Levels
Do not be surprised if you’re ready to stop drinking coffee every day after adapting to the keto diet. Achieving and maintaining ketosis involves benefits like no day slumps, no mood swings, and reducing changes in energy levels that you might experience otherwise.
In addition, you’ll likely find it much easier to remain longer periods of time without feeling hungry. This is what ultimately helps with weight loss, steady blood sugar levels, and extended periods of fasting, which is one of the best ways to get into ketosis.
Enhanced Workouts
Adjusting to the ketogenic diet may take time, however, once your body gets used to burning fat for fuel rather than sugar, or glucose, from carbohydrates, you will likely notice a difference in your physical performance and endurance, such as more energy and focus for workouts. This makes sense because being in ketosis “instructs” the entire human body to burn fat for fuel more efficiently.
The most important first step in case you start the ketogenic diet and notice limitations in your physical performance is to give your body some time to adapt from utilizing carbohydrates as its primary fuel to utilizing ketones as a source of energy. For individuals who participate in a lot of physical activities and exercise as well as athletes may benefit from a cyclical or targeted ketogenic diet.
Fat Loss / Muscle Gain
The amount of protein intake on a ketogenic diet makes it excellent for building muscle mass. Results might seem to come more gradually than for someone fueling their workouts but that is usually because you’re building lean mass together with fat reduction. By way of instance, when documenting a keto fast for four days, the individual gained 2.4 lbs of muscle with 1.1 lbs of fat reduction.
Ketogenic Diet and Mental Clarity
Several research�studies have demonstrated that a ketogenic diet may have the ability to support mental clariy as well as help boost productivity, support better memory, and also, have positive effects in regard to moderate cognitive impairment.
Neurological Support
Early usage of the ketogenic diet has been used as a treatment for reducing seizures in people with epilepsy, especially children. Additionally, it has been shown to benefit people with Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative disorders. This is likely because ketone bodies created through the keto diet can have neuroprotective effects.
Weight loss is one of the most well-known advantages of the ketogenic diet, however, this nutritional plan can have many other health benefits. By reducing the consumption of carbohydrates, the cells will go into a state of ketosis and instead utilize ketones created from fats, providing a steadier supply of energy than that of glucose, or sugar. Furthermore, research studies have also demonstrated the ketogenic diet’s possible role in disease prevention, such as for people with epilepsy. Dr. Alex Jimenez D.C., C.C.S.T. Insight
The benefits of the ketogenic diet are essential, not just for weight loss, but for overall health and wellness. When you are eating more fats and proteins with fewer carbohydrates, you are more likely to end up eating fewer calories. With this, you also don’t experience a change of energy levels but instead maintain a level of energy that lets you remain focused on your everyday tasks.
Regardless of the health goal you have in mind, the ketogenic, or keto, offers many benefits to improve your quality of life. Being aware of the proper foods you should eat on the keto diet is also important. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Curated by Dr. Alex Jimenez
Additional Topic Discussion:�Acute Back Pain
Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �
Have you started following the ketogenic diet? Are you confused with what type of fats you should eat to achieve and maintain ketosis? In the following article, we will list the different types of essential fats which are vital in the ketogenic diet.
Fats are crucial in the ketogenic diet. To promote the breaking down of fat rather than protein or carbohydrates, you need to consume fat, a process known as ketosis. However, the value of the healthy fats you eat is fundamental.�Fat is satiating and it tastes good. Simply, be sure to eat the ideal kind of fat. There are four categories of fat permitted on the ketogenic, or keto, diet:
Polyunsaturated fats
Monounsaturated fats (MUFAs)
Polyunsaturated fats (PUFAs), which comprises omega 3
Only naturally-occurring trans fats
Remember that a balance of omega-3s and omega-6s can help maintain overall health and wellness, improving brain and nerve function and decreasing the risk of cardiovascular disease, Alzheimer’s disease,�and type-2 diabetes. While omega-6 is vital, however, too much of it can cause inflammation in the human body, therefore, avoid eating high amounts of omega-6 from sources like peanuts and vegetable oils, such as corn oil or sunflower oil.
Instead, focus largely on the intake of omega-3s from fish sources like trout, salmon, tuna, and mackerel or take a high-quality fish oil supplement. Additionally, be cautious of seeds and nuts since they do include some carbohydrates, particularly pistachios and almonds. Make certain that the fat you eat�is currently coming out of nutrient-dense foods, such as fatty cuts of meat. Below is a food listing of the major types of fat in the ketogenic diet.
Fats are the basis of the ketogenic diet. The high fat intake and the low fat intake helps achieve and maintain ketosis, or the creation of ketones. Utilizing ketones for fuel, the human body can burn fat instead of sugar or glucose from carbohydrates. Getting and keeping your body in the state of ketosis can provide many health benefits, including weight loss and overall health and wellness. The quality of fats you consume while on the keto diet is essential towards reaching ketosis. The following article discusses the different types of fats you can eat while on the ketogenic diet and which ones you should avoid. Dr. Alex Jimenez D.C., C.C.S.T. Insight
Fats and Oils in the Ketogenic Diet
The value of your dietary fat on keto creates a massive difference in the results that you’ll see. If you are taking an unhealthy approach for your new low-carb diet program, then you will quickly discover reverse health consequences. That is why it’s vital to understand which sources of fat are actually considered safe and healthy to consume on while on the ketogenic diet.
The very first sort of healthy fat to begin including on your keto diet plan is saturated fat. Saturated fat was analyzed and proven to enhance HDL and LDL cholesterol levels, both good and bad cholesterol markers, and it may also strengthen bone density and improve the function of your immune system as well as promote the production of important hormones in the human body.
Saturated fats include:
Grass-fed and organic red meats
High fat dairy like ghee, grass-fed butter, and heavy cream
Lard, tallow, and eggs
These are animal-based saturated fats but there are also plant-based selections like olive oil and MCT oil that could provide you with the wholesome dose of saturated fats that you need to maintain your�well-being. Branching out of healthy unsaturated fats, both monounsaturated fatty acids and polyunsaturated fatty acids can help you accomplish your ketosis objectives. Take a look at the graph below to get a visual of these wholesome oils and fats to focus on if following a ketogenic diet.
Monounsaturated fats include:
Virgin olive oil, avocado oil, and macadamia nut oil (eating avocados and olives also helps you reap these healthy fats)
Certain nuts and seeds
Polyunsaturated fats include:
Nuts and seeds such as walnuts, flaxseeds, chia seeds, sunflower, and pumpkin seeds
Flaxseed oil, sesame oil, fish oil, avocado oil, and krill oil
Fatty fish like trout, mackerel, salmon, and tuna
Fats and Oils to Avoid in the Keto Diet
You will also have to learn that some dietary fats should be avoided altogether. Simply because you are after a high-fat ketogenic diet does not mean that you ought to indulge in each fat you encounter. All fats aren’t created equal. Stay away from unhealthy fats like:
Hydrogenated and partially hydrogenated oils. These fats can be present in packaged foods. They may also increase your risk of developing higher cholesterol, cancer, obesity, and heart disease along with inflammation. If you are relying on packaged foods to get you through the ketogenic diet, check the tag and ditch any foods with them.
Highly processed vegetable oils. Peanut oil, corn oil, canola oil, soybean oil, sunflower oil, and grapeseed oil are fats which seem healthier than they are. These fats are generally created with genetically modified seeds which are possible allergens. Extreme heat can also make these oils go rancid. Additionally, they may leave fatty deposits on your body that may result in heart attacks and premature death. Finally, these oils contain higher levels of omega 6 fatty acids which can lead to chronic inflammation.
Nuts and Seeds in the Ketogenic Diet
Another simple and gratifying way to sneak healthy fats into the ketogenic diet would be to reach for uncooked seeds and nuts. These nutrient powerhouses are packed with essential nutrients, such as magnesium, selenium, and manganese. Seeds and nuts may enhance brain health, fortify your immune system, and assist with digestion and blood sugar control.
They are also high in healthy fats, have a moderate quantity of protein, and are usually low carb, based on the kind you select. Nuts and seeds are also simple to�carry, which makes them among the best snacks when on a keto diet. Some nuts and seeds, however, are better than others. In keto, this implies that they have more fat and less carbohydrates.
The five best nuts in the ketogenic diet include:
Macadamia nuts
Pecans
Brazil nuts
Walnuts
Hazelnuts
Pine nuts, almonds, cashews, and pistachios are also great nuts to include into the ketogenic diet. However, because they have more carbohydrates compared to the top five, they need to be consumed in moderation so that you don’t accidentally tip on your carbohydrate count daily. Consuming one or more one of these nuts as nut butter is a handy way to receive a spoonful of nourishment during snack time. However, you are going to want to practice portion control too since the serving size is really small.
The following best seeds in the ketogenic diet include:�
Pumpkin seeds
Sesame seeds
Sunflower seeds and sunflower seed butter
Tahini (sesame seed paste)
Chia seeds
Flaxseeds
Nuts and Seeds to Avoid in the Keto Diet
Are you wondering why peanuts and peanut butter is not part of the list of ketogenic diet foods? The majority of us have grown up eating and snacking on peanut butter. But a lot of us don’t recognize that peanut butter isn’t really made out of nuts; peanuts are a legume, which is part of the exact same family as peas, soybeans, and lentils. While the macro dysfunction and low-fat level of a serving of peanuts might be like other nuts, that is where their healthy comparison stops.
Peanuts and peanut butter are:
Packed with unnecessary added sugars
Loaded with hydrogenated oils (essentially harmful trans fats)
Low in fat and filled with junk as a replacement
Hard to digest
Covered in pesticides
High in oxalates (which prevent proper nutrient absorption and can lead to kidney stones)
High in inflammatory omega-6 fatty acids
Dairy in the Ketogenic Diet
Most dairy products fit into the “fat” and “protein” category but they are accepted as part of the ketogenic diet as long as you’re not lactose intolerant. Simply make sure you eat the full-fat version and preferably choose organic and raw options, if possible. Dairy is not an extremely important element of a keto�diet. If you are lactose intolerant, you may safely omit it.
For people with dairy sensitivities:
Find hard and long-aged dairy
Use ghee, a butter alternative without the irritating milk solids
Get checked for a casein sensitivity to rule out the other common irritant found in dairy
Other dairy choices can include:
Unflavored greek yogurt, fermented yogurt, and kefir
Hard cheeses like blue cheese, gouda, and parmesan
Semi-hard cheese such as Colby, provolone, and swiss cheese
Softer cheeses like mozzarella, brie, muenster, and Monterey Jack
Cream cheese, mascarpone, creme fraiche, and cottage cheese, which are also okay on a high-fat diet
Dairy to Avoid in the Keto Diet
Very similar to healthy versus unhealthy fats, these dairy things are packed using the wrong ingredients and aren’t good if you are trying to achieve and maintain ketosis. To reach ketosis, avoid these 3 dairy products on the ketogenic diet.
Low fat, reduced fat, and fat-free milk. When fat is removed from dairy, sugar is added to fill in the gaps and make these taste much better. The sugar in these products will prevent you from going into ketosis. Whole milk is not much better, however, with 12.8 grams of carbohydrates per glass, you’re much better off enjoying low carb cheese over a glass of milk.
Half and half. Do not go with this particular half milk/half cream mix either. You are still getting a dose of sugar and less fat, two of which is not ideal for a keto diet. Reach for heavy whipping cream and you won’t hav carbohydrates or sugar to contend with.
Evaporated and condensed milk. Before incorporating these canned milk choices for your next recipe, you need to know these are essentially a cooked down variation of milk syrup and sugar in disguise. Luckily, it is simple to substitute this cooking staple with unsweetened, full-fat, canned coconut milk. Plus, as it is made from coconuts, you also receive healthy saturated fats.
Fats are ultimately essential in the ketogenic diet. Recognizing the different types of fats you can eat while on the keto diet is important in order to help you achieve and maintain ketosis. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Curated by Dr. Alex Jimenez
Additional Topic Discussion:�Acute Back Pain
Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �
Fats are an essential�part of the ketogenic diet since they constitute approximately 70 percent of your dietary calories. However, the type of fat you eat on the ketogenic diet is also important and there may be some confusion regarding good fats and bad fats. The following article discusses exactly what fats you need to include and what fats you must avoid while on the keto diet.
Good Fats on the Ketogenic Diet
The type of “good” fats included while on the ketogenic diet are divided into four groups: saturated fats, monounsaturated fats (MUFAs), polyunsaturated fats (PUFAs), and naturally-occurring trans fats. All fats can be classified into more than one group, however, we classify them according to the most dominant of these mixtures. It’s essential to be able to recognize what type of fat you are eating on the ketogenic diet. Below, we will describe each group of good fat so you can properly implement them into your own food choices.
Saturated Fats
For many years, saturated fats were considered to be detrimental for heart health and we were advised to�limit their�consumption as much as possible. However, recent research studies have demonstrated no substantial connection between saturated fats and the increased risk of cardiovascular disease. As a matter of fact, including healthy saturated fats into your diet can have many benefits.
One type of saturated fat contains medium-chain triglycerides (MCTs), which can be largely found in coconut oil, or in small quantities in butter and palm oil, and it may be digested quite easily by the human body. Medium-chain triglycerides pass through the liver for immediate use as energy when consumed. MCTs are beneficial towards promoting weight loss and improving athletic performance.
Health benefits of saturated fats on the keto diet can include:
Improved HDL and LDL cholesterol levels
Maintenance of bone density
Boosting of immune system health
Support in creation of important hormones like cortisol and testosterone
Raising of HDL (good) cholesterol in the blood to prevent buildup of LDL in the arteries
Improved HDL to LDL ratio
Recommended types of saturated fats while on the ketogenic diet include:
Butter
Red meat
Cream
Lard
Coconut oil
Eggs
Palm oil
Cocoa butter
Monounsaturated Fats
Unlike saturated fats, monounsaturated fats, also referred to as monounsaturated fatty acids or MUFAs,�have been approved as a healthy source of fat for several years. A variety of research studies have connected them to numerous health benefits associated with improved levels of “good” cholesterol and better insulin resistance, among other health benefits, as described below.
Health benefits of MUFAs on the keto diet can include:
Increased HDL cholesterol
Lowered blood pressure
Lowered risk for heart disease
Reduced belly fat
Reduced insulin resistance
Recommended types of MUFAs while on the ketogenic diet include:
Extra virgin olive oil
Avocados and avocado oil
Macadamia nut oil
Goose fat
Lard and bacon fat
Healthy Polyunsaturated Fats
The most important point to keep in mind about eating polyunsaturated fats, also referred to as polyunsaturated fatty acids or PUFAs, on the ketogenic diet is that the specific type you consume actually matters. When heated, some polyunsaturated fats may produce substances that can cause inflammation in the human body, increasing the risk of cardiovascular disease and even cancer.
Many PUFAs must be consumed cold and they should never be utilized for cooking. PUFAs can be found both in very processed oils and in very healthy sources. The right types can additionally provide many health benefits on the ketogenic diet, particularly because several of these include omega 3s and omega 6s, both of which are essential nutrients in a healthy and balanced diet.
Health benefits of PUFAs on the keto diet can include:
Reduced risk of heart disease
Reduced risk of stroke
Lowered risk of autoimmune disorders and other inflammatory diseases
Improved symptoms of depression
Improved symptoms of ADHD
Recommended types of PUFAs while on the ketogenic diet include:
Extra virgin olive oil
Flaxseeds and flaxseed oil
Walnuts
Fatty fish and fish oil
Sesame oil
Chia seeds
Nut oils
Avocado oil
Naturally-Occurring Trans Fats
Many people might be confused to see trans fats classified as “good” fats. While most trans fats are considered to be extremely unhealthy and even harmful, one type of trans fat, known as vaccenic acid, can be found naturally in various kinds of food, such as in grass-fed animal products and dairy fats. These naturally-occurring trans fats also provide several health benefits on the keto diet.
Health benefits of naturally-occurring trans fats on the keto diet include:
Reduced risk of heart disease
Reduced risk of diabetes and obesity
Possible protection against cancer risk
Recommended types of naturally-occurring trans fats while on the ketogenic diet include:
Grass-fed animal products
Dairy fats like butter and yogurt
When following a ketogenic diet, or any other low carb diet, eating the right type of fat is essential, especially since these make up about 70 percent of your daily caloric intake. The type of fat you eat is classified into various groups depending on the dominant amount found in the mixture. Extra Virgin Olive Oil, for example, is approximately 73 percent monounsaturated fat, therefore, it is considered a monounsaturated fat. Butter is about 65 percent saturated fat and thus, is a saturated fat.�It’s essential to be able to recognize what type of fat you are eating on the ketogenic diet in order to enjoy its health benefits. Dr. Alex Jimenez D.C., C.C.S.T. Insight
Bad Fats on the Ketogenic Diet
One of the greatest advantages of the ketogenic diet is the capacity to eat lots of satisfying dietary fats such as those mentioned previously. However, we have to also cover the kinds of fats that you should reduce or eliminate from your diet in order to prevent damaging your�well-being. On the keto diet, the quality of food you eat is especially important to achieve ketosis.
Unhealthy Polyunsaturated Fats and Processed Trans Fats
Processed trans fats are the group of fat which most people as the “bad” fats and the truth is, they can actually be quite damaging to your overall health and wellness.� Artificial trans fats are made during food production via the processing of polyunsaturated fats. That is the reason why it’s very important to choose PUFAs which are unprocessed and not overheated or modified. The consumption of unhealthy PUFAs can create harmful free radicals where processed trans fats often contain genetically modified seeds.
Health risks of unhealthy polyunsaturated fats and processed trans fats include:
Increased risk of heart disease
Increased risk of cancer
Reduced HDL cholesterol and increased LDL cholesterol
Pro-inflammatory
Bad for the health of your gut
Examples of unhealthy polyunsaturated fats and processed trans fats to avoid include:
Hydrogenated and partially hydrogenated oils found in processed products like cookies, crackers, margarine, and fast food
Processed vegetable oils like cottonseed, sunflower, safflower, soybean, and canola oils
In conclusion, it’s essential to recognize what type of fat you are eating while on the ketogenic diet. In the end, the function of the ketogenic diet will always be to enhance your health, which includes eating the appropriate amount of fat, protein, and carbohydrate ratio as well as picking food resources which promote health and wellness. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Curated by Dr. Alex Jimenez
Additional Topic Discussion:�Acute Back Pain
Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �
Ketones serve as a source of energy for the mitochondria found inside the cells of the human body. These are an alternative fuel to sugar. Ketones are basic substances with a simple molecular structure. Ketones are natural,�or carbon-based, chemicals made up of a central carbon atom double-bonded into an oxygen atom and two carbon-containing substituents, denoted by”R”.
Genetic Ketone Structure
In humans, there are 3 distinct ketones created by the mitochondria. These are referred to as ketone bodies. The 3 ketones are:
Acetone
Acetoacetate, also known as Acetoacetic Acid
Beta-Hydroxybutyric Acid, also known as Beta Hydroxybutyrate or BHB. Additional compound names include 3-hydroxybutyric acid or 3-hydroxybutyrate.
BHB isn’t particularly considered a ketone because it comprises a reactive OH-group rather than a double-bonded oxygen which would generally function as demonstrated in the diagram below. However, BHB continues to function much like a ketone because it transforms into energy, such as acetone and acetoacetate. The following is demonstrated in the diagram below.
Structures of Ketone Bodies
Ketogenesis is the metabolism of fatty acids through ?-oxidation. This procedure provides acetyl CoA which converts to ?-hydroxy-?-methyglutaryl-CoA, or HMG-CoA, as shown below. HMG-CoA turns into Acetoacetone which may change back-and-forth to BHB. The conversion of Acetoacetate into Acetone is irreversible (as seen on the bottom left). Acetoacetate and BHB, through acetoacetate, are utilized to make energy when converted into acetyl-CoA in the cell’s mitochondria whilst Acetone is excreted in the breath and urine.
Formation of Ketone Bodies from Acetyl-CoA2
Understanding Exogenous Ketone Bodies
Exogenous ketone bodies are simply ketone bodies which are consumed via a nutritional supplement. Ketone bodies created in the liver are more correctly referred to as endogenous ketone bodies. The following is described below.
Most nutritional supplements depend�on BHB as the origin of the exogenous ketone bodies. BHB transforms into acetoacetic acid where a small amount is turned into acetone via an acetoacetate decarboxylase waste pathway. A percentage of that acetoacetic acid may enter the energy pathway utilizing beta-ketothialase, which transforms acetoacetic acid into 2 Acetyl-CoA molecules.
Ketosis Pathway Before Entering the Krebs (Energy) Pathway
The Acetyl-CoA will then enter the Krebs cycle and creates ATP. Exogenous ketone body nutritional supplements provide an instantaneous supply of ketones to consumers. Even when you’re not in the state of ketosis before eating, such as when ingesting a higher-carb diet. These also increase blood ketones even in the presence of insulin, which inhibits ketogenesis.
Researchers do not completely comprehend what the long-term ramifications of combining a non-ketogenic diet with exogenous ketone bodies nutritional supplements really are. Research studies are at their first phases and much more information is required. A standard issue involves why BHB is the ketone body to receive exogenous ketone nutritional supplements. The explanation is a mixture in the simplicity of its formula and its conversion to energy. it is simpler to devise BHB into a nutritional supplement.
Are “Raspberry Ketones” Similar to “Ketone Bodies”?
Raspberry ketones are a�common ingredient used in weight-loss nutritional supplements. However, despite their title, they don’t have any connection. This has generated some confusion for individuals considering ketone nutritional supplements that are exogenous.
Raspberry ketones are in reality phenolic compounds that provide raspberries their pleasant odor. They are similar to the stimulant synephrine. Regardless of the research studies, raspberry ketones don’t seem to have much impact on weight loss.
Ketone Salts vs. Ketone Esters
Exogenous ketones of all beta-hydroxybutyrate can be found in two kinds:
Ketone Salts are naturally-derived chemicals which blend sodium as well as potassium and/or calcium with BHB to boost absorption. Commercially available nutritional supplements are all created from ketone salts now (contains KetoForce, KetoCaNa and Keto OS). These are also occasionally called “Ketone Mineral Salts” or “BHB Mineral Salts”.
Ketone Esters are Synthetically-made chemicals that connect an alcohol to a ketone body, where this can be metabolized in the liver as a ketone. Ketone esters are used primarily in search for testing their effectiveness on improving ketone body levels. Below is a standard arrangement of a BHB ester. The very first Ketone Ester beverage is currently accessible by HVMN. Research esters are very unpleasant tasting, something which HVMN expects to modify soon.
Structure of a Beta-Hydroxybutyrate Ester
Ketone Esters increase blood levels of beta-hydroxybutyrate to greater levels compared to Ketone Salts. There’s strong evidence supporting that esters are more powerful than Ketone Salts, so much as their advantages proceed. It’s not apparent why this occurs, but it might be from the gastrointestinal, or GI, tract due to a gap in the absorption rate.
However, esters are normally somewhat tougher to endure because of gut distress after intake and they do not have the most agreeable taste, as stated previously in the article. Figure 1 below demonstrates the difference between eating equivalent quantities of BHB in the kind of a Ketone ester and Ketone salts on bloo BHB. The supplements contained are:
BMS (Beta-hydroxybutyrate Mineral Salt) — sodium/ potassium established (KetoForce)
KE (Ketone Ester) — (R- 3-hydroxybutyl-R-1,3-hydroxybutyrate) (HVMN)
Figure 1: Blood BHB level after consuming a ketone ester vs a ketone salt drink.
What are the Benefits of Exogenous Ketones?
Exogenous ketone nutritional supplements can offer a great number of benefits. These include more effective weight reduction, athletic performance improvement, cancer prevention, cognitive advancement,�and anti-inflammatory properties.
Weight Loss Goals
Appetite suppression: Appetite was quantified in 10 males and 5 females after taking a ketone ester, abbreviated as KE, or a dextrose, abbreviated as DEXT, beverage. The wish to consume and perception of appetite dropped after both supplements, however, the KE was 50 percent more successful for 1.5 to 4 hours. Insulin levels rose with both supplements but were 3 times lower with the KE beverage after 30 minutes, according to Figure 2. The desire hormone, ghrelin, was considerably lower between 2 to 4 hours after ingesting the KE, as seen on Figure 2. Ketone esters lower the urge and delays appetite.
Figure 2: Perceived hunger, fullness, and satiety after consuming a dextrose or ketone ester drink over time. Effects of ketone ester or dextrose drink on plasma insulin and ghrelin levels over time.
Extra ketones: In case someone has an inordinate number of ketones in the bloodstream, the human body, especially the kidneys, will function as swiftly as possible to filter out ketones via urine instead of converting them into adipose tissue. This isn’t to say you can not gain fat with�exogenous ketones, however, they are not as inclined to be converted into fat than other nourishment.
More tolerable compared to MCT oil: MCT oil was known to cause gastrointestinal distress in consumers, particularly when taken in high quantities. Exogenous ketones as ketone salts are well-tolerated. They prevent adverse GI events while supplying similar kinds of benefits. Figure 2 demonstrates how Ketone esters may be capable of reducing hunger. A combo of exogenous ketones and MCT oil can help with weight loss and permit a loading of nutritional supplements, with no GI distress.
Athletic Performance Goals
Athletic enhancem: The development of energy and�fuel pairing mechanisms. Exogenous ketone supplementation may boost these components of athletic performance. There’s a promising prognosis in this area for many different motives:
Exogenous ketones induce severe ketosis, lasting for many hours. This is without having to possess depleted muscle glycogen stores. Low muscle nourishment is well-known to inhibit sustained physical functionality.
The “carb-sparing” impact from BHB inhibits the breakdown of muscle glycogen. This contributes to reduced lactate levels. When raising exercise intensity, fat oxidation, or burning, reaches a limit. Carbohydrates are then burned�for energy.�But when swallowing Ketone esters, the body doesn’t make this change. This implies ketones are used instead.
Exogenous ketones induce your system to rely on fat as fuel, as seen in Figure 3. Fat takes longer to metabolize compared to muscle glycogen for vitality. That is because fatty acids aren’t the fuel that is favored by the human body under exercise. This might be useful for athletes performing resistance training or cardiovascular exercises. This is especially helpful for�athletes that would like to experience cardiovascular or resistance training.
Ketone esters boost free carnitine whilst exercising which appears to enhance physical performance.
Exogenous ketones decrease the usage of Branched-chain amino acids, or BCAAs, as�energy, a process known as deamination. The growth was decreased by consumption of a ester beverage by 50 percent during exercise in muscle BCAAs.
Figure 3: Plasma free fatty acid (FFA) and glycerol concentrations after consuming high fat, carbohydrate, or ketone ester drink.
Increased cognition: Elevated plasma ketone concentrations divert the brain to use ketone bodies for the synthesis of phospholipids, which drives growth and myelination. Sugar is often the preferred�fuel for this process, which is not as efficient. BHB appears to work as a signal for pathways. These improve cognition, plasticity and stress immunity. In rat research studies, ingestion of a ketone ester for 5 days enhanced memory and their learning.
Health & Longevity
Anti-carcinogenic properties: Statistics appears to imply that exogenous ketones are a powerful anti-carcinogen. The motive for this is that cancer cells cannot utilize ketone bodies efficiently. In fact ketone supplementation was demonstrated to improve survival rates of mice with cancer.
Neuroprotection: As people age, the brain becomes more prone to neurodegeneration and following conditions like Alzheimer’s and Parkinson’s disease. Ketone supplementation seems to ameliorate the decline. The mechanism is that ketone bodies decrease hyperexcitability and the redness that’s ordinarily shown as sugar metabolism declines from the brain.
Anti-Inflammatory attributes: There’s proof that ketone bodies play an essential part in reducing inflammation by inhibiting a particular class of proteins known as inflammasones.
Gene regulation profile alterations: There’s proof that gene sets could be regulated with an alteration in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, or mHS, as see in rats on a ketogenic diet.
Ketones are a source of energy which is produced when there is not enough sugar or glucose for the human body to burn as fuel. They serve as an alternative fuel source to glucose. Ketogenesis, the metabolism of fatty acids through ketosis, can have a variety of health benefits. Many people achieve these benefits by following the ketogenic diet, however, these advantages can be achieved without the keto diet as well. Exogenous ketone bodies are simply ketones which are consumed through a nutritional supplement. Although the over-consumption of any supplement can have risks, exogenous ketone bodies can provide similar benefits to ketosis. Dr. Alex Jimenez D.C., C.C.S.T. Insight
How Exogenous Ketones Function
Exogenous ketones possess many different physiological effects soon after ingestion:
For starters, ingesting ketones, particularly ketone esters, is an effective approach to Boost BHB from the bloodstream above 2 mMol for almost 8 hours. Ketone salts do not seem to elevate BHB from the bloodstream as efficiently or significantly where ketone esters do, however.
Exogenous ketone supplementation induces blood sugar to reduce significantly, likely as a result of an intense increase in insulin sensitivity. Exogenous ketones may pose a possible treatment.
Exogenous ketones additionally improve oxygen use, particularly in the central nervous system, or CNS. This effect reduces the odds of oxygen reaching potentially hazardous levels in the CNS, which then has a variety of additional favorable health effects like the ones discussed in the prior section.
Potential Downsides to Ketone Supplementation
Like any other nutritional supplement, side effects and drawbacks are possible after consuming exogenous ketones. As ketone supplementation becomes more notable, they are generally quite benign and will improve. The most frequent side effects to know about when using exogenous ketones consist of:
Electrolyte Imbalance: The physiological rationale supporting electrolytes during a state of ketosis is a result of the absence of water retention and frequent urination. The frequency of urination will�increase when supplementing exogenous ketones, but it will not deplete glycogen stores. It could be handy after taking ketones if you’re urinating a lot to drink an electrolyte solution, but it is dependent upon the way you are feeling.
Halitosis or bad breath: If you are on a ketogenic diet, you’re most likely aware that since the body begins to metabolize fat, ketones may cause bad breath. There is little one can do about this. This may arise when utilizing exogenous ketones, but it is not quite as durable as when on the ketogenic diet. If it turns into a problem, chewing gum or mints is the best choice. This issue may occur due to the over-consumption of this nutritional supplement, tailoring extra BHB.
Potential GI distress (flatulence) at exceptionally substantial doses: Exogenous ketones taken in massive doses sometimes lead to GI distress, particularly flatulence. On the other hand, this cause can be hypothesized to be a result of how ketones were blended in a fluid which was palatable. If you are taking a balanced dose of ketones GI distress can be avoided. If some GI distress is widespread, it must improve as you become accustomed to carrying ketones.
Hypoglycemia: Accepting exogenous ketones can induce blood sugar levels to become very low, but you’re unlikely to feel the normal signs of hypoglycemia. That is because if levels are large enough, they control energy in the brain; despite having low blood sugar, therefore, you may feel just fine. A research by George Cahill, discovered that if they had been administered insulin to induce hypoglycemia, ketone levels can protect fasted participants.
Future Research Studies
Research studies on exogenous ketones concentrates on the advantages of their use. Research studies will also concentrate more on their therapeutic use. The information on all those applications is currently limited. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Curated by Dr. Alex Jimenez
Additional Topic Discussion:�Acute Back Pain
Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �
Cancer is the second leading cause of death in the United States. Research studies have estimated that approximately 595,690 Americans die from cancer every year, that’s about 1,600 deaths every day, on average. Cancer is frequently treated utilizing a combination of surgery, chemotherapy, and radiation. Recent research studies have analyzed a variety of nutritional strategies for cancer treatment. Early research studies suggest�that the ketogenic diet may help treat cancer.
What is the Ketogenic Diet?
The ketogenic diet is a very low-carb, high-fat diet which is often compared with the Atkins diet and other low carb diets. Also commonly known as the keto diet, this nutritional strategy entails drastically reducing your consumption of carbohydrates and instead substituting them with fat. This dietary shift is what causes the human body to enter a state of ketosis, the well-known metabolic state associated with the keto�diet. Ketosis utilizes fat as the cell’s main source of energy, rather than sugar or glucose.
Ketosis causes a considerable increase in the levels of ketones. In general, a ketogenic diet used for weight loss consists of about 60 to 75 percent of calories from fat, with 15 to 30 percent of calories from protein and 5 to 10 percent of calories from carbohydrates. However, when a ketogenic diet is used therapeutically to treat cancer, the fat content might be significantly higher, up to 90 percent of calories from fat, and the protein content will also be considerably lower, up to 5 percent of calories from protein.
The Role of Blood Sugar in Cancer
Many cancer treatments are designed to target the biological differences between cancer cells and normal cells. Nearly all cancer cells share one common characteristic: they feed off of blood sugar or glucose in order to grow and multiply. During the ketogenic diet, several conventional metabolic processes are modified and blood sugar levels decrease, “starving” cancer cells. As a result, cancer cells have been demonstrated to grow much slower, often decreasing in size or even dying.
This nutritional strategy as a form of cancer treatment was first proposed by Otto Heinrich Warburg,�a leading cell biologist. Otto Warburg led to the discovery that cancer cells are unable to flourish using energy produced from cellular respiration but instead from glucose fermentation. The Warburg effect developed from the role of glycolysis and lactic acid fermentation to transfer energy, compensating for lower dependence on oxidative phosphorylation and limited mitochondrial respiration.
Benefits of the Keto�Diet for Cancer
The ketogenic diet provides other benefits in cancer treatment. Primarily, reducing carbohydrates from your diet can quickly lower calorie intake, reducing the energy available to the cells. In turn, this may slow down tumor development and the progression of cancer. Additionally, the ketogenic diet may help lower insulin levels. Insulin is an anabolic hormone which promotes cell growth, including cancerous cells. Therefore, lower insulin may help slow down tumor development.
The Ketogenic Diet and Cancer in Animals
Researchers have analyzed the ketogenic diet as an alternative cancer treatment for many decades. Until recently, most research studies�were performed in animals. A big number of these animal research studies have demonstrated that the ketogenic diet can reduce tumor growth and improve survival levels in mice.
One research study in mice reviewed the cancer-fighting effects of the ketogenic diet along with other diets. Strikingly, the researchers found that 60 percent of mice following the ketogenic diet survived. This increased to 100 percent in mice that received a ketone supplement while on the keto�diet. None lived on a standard diet.
The Ketogenic Diet and Cancer in Humans
Despite the promising evidence of the benefits of the ketogenic diet as a form of cancer treatment in animals, research studies in humans have only just started. At present, the limited research studies does seem to demonstrate that a ketogenic diet may decrease tumor size and decrease the progression�of certain cancers. One of the few documented cases was conducted on a 65-year-old woman with brain cancer. Following surgery, she followed a ketogenic diet and the tumor’s progression decreased.
However, 10 weeks after returning to a normal diet, she experienced a substantial increase in tumor growth. Similar case reports analyzed the reactions to a ketogenic diet in two women who were undergoing therapy for advanced brain cancer. Researchers discovered that glucose uptake was decreased from the tumors of both patients. One of the women reported improved quality of life and stayed on the diet for 12 weeks. During that time her disease showed no further progression.
One research study tracked tumor growth in response to a high-carbohydrate diet versus a ketogenic diet in 27 patients with gastrointestinal cancer. Tumor growth increased by 32.2 percent in patients who received the high-carb diet while tumor growth decreased by 24.3 percent in patients on the ketogenic diet. In a different research study, three out of five patients on a ketogenic diet combined with radiation or chemotherapy experienced complete remission.
Can the Ketogenic Diet Help Prevent Cancer?
A variety of research studies have also demonstrated that the ketogenic diet can help prevent cancer in the first place. Primarily, it can help reduce several risk factors for cancer. The keto diet may help decrease IGF-1 levels. Insulin-like growth factor 1, or IGF-1, is a hormone that’s essential for cell growth while reducing programmed cell death. This hormone can play a part in the evolution and progression of cancer. The ketogenic diet is thought to decrease IGF-1 levels, thereby decreasing the effects insulin has on cell growth, reducing the risk of cancer.
The ketogenic diet can also help lower blood sugar levels and decrease the risk of diabetes. Other evidence indicates that people with elevated glucose and diabetes have an increased risk of developing cancer. Research studies show that a ketogenic diet can be extremely effective at lowering blood sugar levels and handling diabetes. The keto diet can reduce obesity. Obesity can be a risk factor for cancer. Since the ketogenic diet is a powerful weight loss tool, it may also help reduce the chance of cancer by fighting obesity.
Emerging research studies continue to demonstrate that sugar or glucose is the main source of fuel for cancer. Researchers have attempted to demonstrate that regulating the metabolic functions within the human body is the real solution towards treating cancer. The ketogenic diet can help treat cancer because it limits the amount of sugar in the body and instead replaces it with ketones, “starving” cancer cells and decreasing cell growth and cancer progression. Dr. Alex Jimenez D.C., C.C.S.T. Insight
Conclusion
A ketogenic diet offers many health advantages. Based on animal and early research studies in humans, it may also serve as a cancer treatment. However, it’s important to keep in mind that further research studies are still required to conclude the effects of the ketogenic diet on cancer. You shouldn’t avoid conventional cancer therapy in favor of an alternative treatment option like the keto�diet.�The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Curated by Dr. Alex Jimenez
Additional Topic Discussion:�Acute Back Pain
Back pain�is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as�herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief. �
Ketone bodies are created by the liver and utilized as an energy source when glucose is not readily available in the human body. The two main ketone bodies are acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB), while acetone is the third and least abundant, ketone body. Ketones are always present in the blood and their levels increase during fasting and prolonged exercise.�Ketogenesis is the biochemical process by which organisms produce ketone bodies through the breakdown of fatty acids and ketogenic amino acids.
Ketone bodies are mainly generated in the mitochondria of liver cells. Ketogenesis occurs when there are low glucose levels in the blood, particularly after other cellular carbohydrate stores, such as glycogen, have been exhausted. This mechanism can also occur when there is insufficient amounts of insulin. The production of ketone bodies is ultimately initiated to make available energy which is stored in the human body as fatty acids. Ketogenesis occurs in the mitochondria where it is independently regulated.
Abstract
Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient remains and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, recent observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.
Introduction
Ketone bodies are a vital alternative metabolic fuel source for all the domains of life, eukarya, bacteria, and archaea (Aneja et al., 2002; Cahill GF Jr, 2006; Krishnakumar et al., 2008). Ketone body metabolism in humans has been leveraged to fuel the brain during episodic periods of nutrient deprivation. Ketone bodies are interwoven with crucial mammalian metabolic pathways such as ?-oxidation (FAO), the tricarboxylic acid cycle (TCA), gluconeogenesis, de novo lipogenesis (DNL), and biosynthesis of sterols. In mammals, ketone bodies are produced predominantly in the liver from FAO-derived acetyl-CoA, and they are transported to extrahepatic tissues for terminal oxidation. This physiology provides an alternative fuel that is augmented by relatively brief periods of fasting, which increases fatty acid availability and diminishes carbohydrate availability (Cahill GF Jr, 2006; McGarry and Foster, 1980; Robinson and Williamson, 1980). Ketone body oxidation becomes a significant contributor to overall energy mammalian metabolism within extrahepatic tissues in a myriad of physiological states, including fasting, starvation, the neonatal period, post-exercise, pregnancy, and adherence to low carbohydrate diets. Circulating total ketone body concentrations in healthy adult humans normally exhibit circadian oscillations between approximately 100�250 �M, rise to ~1 mM after prolonged exercise or 24h of fasting, and can accumulate to as high as 20 mM in pathological states like diabetic ketoacidosis (Cahill GF Jr, 2006; Johnson et al., 1969b; Koeslag et al., 1980; Robinson and Williamson, 1980; Wildenhoff et al., 1974). The human liver produces up to 300 g of ketone bodies per day (Balasse and Fery, 1989), which contribute between 5�20% of total energy expenditure in fed, fasted, and starved states (Balasse et al., 1978; Cox et al., 2016).
Recent studies now highlight imperative roles for ketone bodies in mammalian cell metabolism, homeostasis, and signaling under a wide variety of physiological and pathological states. Apart from serving as energy fuels for extrahepatic tissues like brain, heart, or skeletal muscle, ketone bodies play pivotal roles as signaling mediators, drivers of protein post-translational modification (PTM), and modulators of inflammation and oxidative stress. In this review, we provide both classical and modern views of the pleiotropic roles of ketone bodies and their metabolism.
Overview of Ketone Body Metabolism
The rate of hepatic ketogenesis is governed by an orchestrated series of physiological and biochemical transformations of fat. Primary regulators include lipolysis of fatty acids from triacylglycerols, transport to and across the hepatocyte plasma membrane, transport into mitochondria via carnitine palmitoyltransferase 1 (CPT1), the ?-oxidation spiral, TCA cycle activity and intermediate concentrations, redox potential, and the hormonal regulators of these processes, predominantly glucagon and insulin [reviewed in (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983; Kahn et al., 2005; McGarry and Foster, 1980; Williamson et al., 1969)]. Classically ketogenesis is viewed as a spillover pathway, in which ?-oxidation-derived acetyl-CoA exceeds citrate synthase activity and/or oxaloacetate availability for condensation to form citrate. Three-carbon intermediates exhibit anti-ketogenic activity, presumably due to their ability to expand the oxaloacetate pool for acetyl-CoA consumption, but hepatic acetyl-CoA concentration alone does not determine ketogenic rate (Foster, 1967; Rawat and Menahan, 1975; Williamson et al., 1969). The regulation of ketogenesis by hormonal, transcriptional, and post-translational events together support the notion that the molecular mechanisms that fine-tune ketogenic rate remain incompletely understood (see Regulation of HMGCS2 and SCOT/OXCT1).
Ketogenesis occurs primarily in hepatic mitochondrial matrix at rates proportional to total fat oxidation. After transport of acyl chains across the mitochondrial membranes and ?-oxidation, the mitochondrial isoform of 3-hydroxymethylglutaryl-CoA synthase (HMGCS2) catalyzes the fate committing condensation of acetoacetyl-CoA (AcAc-CoA) and acetyl-CoA to generate HMG-CoA (Fig. 1A). HMG-CoA lyase (HMGCL) cleaves HMG-CoA to liberate acetyl-CoA and acetoacetate (AcAc), and the latter is reduced to d-?-hydroxybutyrate (d-?OHB) by phosphatidylcholine-dependent mitochondrial d-?OHB dehydrogenase (BDH1) in a NAD+/NADH-coupled near-equilibrium reaction (Bock and Fleischer, 1975; LEHNINGER et al., 1960). The BDH1 equilibrium constant favors d-?OHB production, but the ratio of AcAc/d-?OHB ketone bodies is directly proportional to mitochondrial NAD+/NADH ratio, and thus BDH1 oxidoreductase activity modulates mitochondrial redox potential (Krebs et al., 1969; Williamson et al., 1967). AcAc can also spontaneously decarboxylate to acetone (Pedersen, 1929), the source of sweet odor in humans suffering ketoacidosis (i.e., total serum ketone bodies > ~7 mM; AcAc pKa 3.6, ?OHB pKa 4.7). The mechanisms through which ketone bodies are transported across the mitochondrial inner membrane are not known, but AcAc/d-?OHB are released from cells via monocarboxylate transporters (in mammals, MCT 1 and 2, also known as solute carrier 16A family members 1 and 7) and transported in the circulation to extrahepatic tissues for terminal oxidation (Cotter et al., 2011; Halestrap and Wilson, 2012; Halestrap, 2012; Hugo et al., 2012). Concentrations of circulating ketone bodies are higher than those in the extrahepatic tissues (Harrison and Long, 1940) indicating ketone bodies are transported down a concentration gradient. Loss-of-function mutations in MCT1 are associated with spontaneous bouts of ketoacidosis, suggesting a critical role in ketone body import.
� With the exception of potential diversion of ketone bodies into non-oxidative fates (see Non-oxidative metabolic fates of ketone bodies), hepatocytes lack the ability to metabolize the ketone bodies they produce. Ketone bodies synthesized de novo by liver are (i) catabolized in mitochondria of extrahepatic tissues to acetyl-CoA, which is available to the TCA cycle for terminal oxidation (Fig. 1A), (ii) diverted to the lipogenesis or sterol synthesis pathways (Fig. 1B), or (iii) excreted in the urine. As an alternative energetic fuel, ketone bodies are avidly oxidized in heart, skeletal muscle, and brain (Balasse and Fery, 1989; Bentourkia et al., 2009; Owen et al., 1967; Reichard et al., 1974; Sultan, 1988). Extrahepatic mitochondrial BDH1 catalyzes the first reaction of ?OHB oxidation, converting it to back AcAc (LEHNINGER et al., 1960; Sandermann et al., 1986). A cytoplasmic d-?OHB-dehydrogenase (BDH2) with only 20% sequence identity to BDH1 has a high Km for ketone bodies, and also plays a role in iron homeostasis (Davuluri et al., 2016; Guo et al., 2006). In extrahepatic mitochondrial matrix, AcAc is activated to AcAc-CoA through exchange of a CoA-moiety from succinyl-CoA in a reaction catalyzed by a unique mammalian CoA transferase, succinyl-CoA:3-oxoacid-CoA transferase (SCOT, CoA transferase; encoded by OXCT1), through a near equilibrium reaction. The free energy released by hydrolysis of AcAc-CoA is greater than that of succinyl-CoA, favoring AcAc formation. Thus ketone body oxidative flux occurs due to mass action: an abundant supply of AcAc and rapid consumption of acetyl-CoA through citrate synthase favors AcAc-CoA (+ succinate) formation by SCOT. Notably, in contrast to glucose (hexokinase) and fatty acids (acyl-CoA synthetases), the activation of ketone bodies (SCOT) into an oxidizable form does not require the investment of ATP. A reversible AcAc-CoA thiolase reaction [catalyzed by any of the four mitochondrial thiolases encoded by either ACAA2 (encoding an enzyme known as T1 or CT), ACAT1 (encoding T2), HADHA, or HADHB] yields two molecules of acetyl-CoA, which enter the TCA cycle (Hersh and Jencks, 1967; Stern et al., 1956; Williamson et al., 1971). During ketotic states (i.e., total serum ketones > 500 �M), ketone bodies become significant contributors to energy expenditure�and are utilized in tissues rapidly until uptake or saturation of oxidation occurs (Balasse et al., 1978; Balasse and Fery, 1989; Edmond et al., 1987). A very small fraction of liver-derived ketone bodies can be readily measured in the urine, and utilization and reabsorption rates by the kidney are proportionate to circulating concentration (Goldstein, 1987; Robinson and Williamson, 1980). During highly ketotic states (> 1 mM in plasma), ketonuria serves as a semi-quantitative reporter of ketosis, although most clinical assays of urine ketone bodies detect AcAc but not ?OHB (Klocker et al., 2013).
Ketogenic Substrates and their Impact on Hepatocyte Metabolism
Ketogenic substrates include fatty acids and amino acids (Fig. 1B). The catabolism of amino acids, especially leucine, generates about 4% of ketone bodies in post-absorptive state (Thomas et al., 1982). Thus the acetyl-CoA substrate pool to generate ketone bodies mainly derives from fatty acids, because during states of diminished carbohydrate supply, pyruvate enters the hepatic TCA cycle primarily via anaplerosis, i.e., ATP-dependent carboxylation to oxaloacetate (OAA), or to malate (MAL), and not oxidative decarboxylation to acetyl-CoA (Jeoung et al., 2012; Magnusson et al., 1991; Merritt et al., 2011). In liver, glucose and pyruvate contribute negligibly to ketogenesis, even when pyruvate decarboxylation to acetyl-CoA is maximal (Jeoung et al., 2012).
Acetyl-CoA subsumes several roles integral to hepatic intermediary metabolism beyond ATP generation via terminal oxidation (also see The integration of ketone body metabolism, post-translational modification, and cell physiology). Acetyl-CoA allosterically activates (i) pyruvate carboxylase (PC), thereby activating a metabolic control mechanism that augments anaplerotic entry of metabolites into the TCA cycle (Owen et al., 2002; Scrutton and Utter, 1967) and (ii) pyruvate dehydrogenase kinase, which phosphorylates and inhibits pyruvate dehydrogenase (PDH) (Cooper et al., 1975), thereby further enhancing flow of pyruvate into the TCA cycle via anaplerosis. Furthermore, cytoplasmic acetyl-CoA, whose pool is augmented by mechanisms that convert mitochondrial acetyl-CoA to transportable metabolites, inhibits fatty acid oxidation: acetyl-CoA carboxylase (ACC) catalyzes the conversion of acetyl-CoA to malonyl-CoA, the lipogenic substrate and allosteric inhibitor of mitochondrial CPT1 [reviewed in (Kahn et al., 2005; McGarry and Foster, 1980)]. Thus, the mitochondrial acetyl-CoA pool both regulates and is regulated by the spillover pathway of ketogenesis, which orchestrates key aspects of hepatic intermediary metabolism.
Non-Oxidative Metabolic Fates of Ketone Bodies
The predominant fate of liver-derived ketones is SCOT-dependent extrahepatic oxidation. However, AcAc can be exported from mitochondria and utilized in anabolic pathways via conversion to AcAc-CoA by an ATP-dependent reaction catalyzed by cytoplasmic acetoacetyl-CoA synthetase (AACS, Fig. 1B). This pathway is active during brain development and in lactating mammary gland (Morris, 2005; Robinson and Williamson, 1978; Ohgami et al., 2003). AACS is also highly expressed in adipose tissue, and activated osteoclasts (Aguilo et al., 2010; Yamasaki et al., 2016). Cytoplasmic AcAc-CoA can be either directed by cytosolic HMGCS1 toward sterol biosynthesis, or cleaved by either of two cytoplasmic thiolases to acetyl-CoA (ACAA1 and ACAT2), carboxylated to malonyl-CoA, and contribute to the synthesis of fatty acids (Bergstrom et al., 1984; Edmond, 1974; Endemann et al., 1982; Geelen et al., 1983; Webber and Edmond, 1977).
While the physiological significance is yet to be established, ketones can serve as anabolic substrates even in the liver. In artificial experimental contexts, AcAc can contribute to as much as half of newly synthesized lipid, and up to 75% of new synthesized cholesterol (Endemann et al., 1982; Geelen et al., 1983; Freed et al., 1988). Because AcAc is derived from incomplete hepatic fat oxidation, the ability of AcAc to contribute to lipogenesis in vivo would imply hepatic futile cycling, where fat-derived ketones can be utilized for lipid production, a notion whose physiological significance requires experimental validation, but could serve adaptive or maladaptive roles (Solinas et al., 2015). AcAc avidly supplies cholesterogenesis, with a low AACS Km-AcAc (~50 �M) favoring AcAc activation even in the fed state (Bergstrom et al., 1984). The dynamic role of cytoplasmic ketone metabolism has been suggested in primary mouse embryonic neurons and in 3T3-L1 derived-adipocytes, as AACS knockdown impaired differentiation of each cell type (Hasegawa et al., 2012a; Hasegawa et al., 2012b). Knockdown of AACS in mice in vivo decreased serum cholesterol (Hasegawa et al., 2012c). SREBP-2, a master transcriptional regulator of cholesterol biosynthesis, and peroxisome proliferator activated receptor (PPAR)-? are AACS transcriptional activators, and regulate its transcription during neurite development and in the liver (Aguilo et al., 2010; Hasegawa et al., 2012c). Taken together, cytoplasmic ketone body metabolism may be important in select conditions or disease natural histories, but are inadequate to dispose of liver-derived ketone bodies, as massive hyperketonemia occurs in the setting of selective impairment of the primary oxidative fate via loss of function mutations to SCOT (Berry et al., 2001; Cotter et al., 2011).
Regulation of HMGCS2 and SCOT/OXCT1
The divergence of a mitochondrial from the gene encoding cytosolic HMGCS occurred early in vertebrate evolution due to the need to support hepatic ketogenesis in species with higher brain to body weight ratios (Boukaftane et al., 1994; Cunnane and Crawford, 2003). Naturally occurring loss-of-function HMGCS2 mutations in humans cause bouts of hypoketotic hypoglycemia (Pitt et al., 2015; Thompson et al., 1997). Robust HMGCS2 expression is restricted to hepatocytes and colonic epithelium, and its expression and enzymatic activity are coordinated through diverse mechanisms (Mascaro et al., 1995; McGarry and Foster, 1980; Robinson and Williamson, 1980). While the full scope of physiological states that influence HMGCS2 requires further elucidation, its expression and/or activity is regulated during the early postnatal period, aging, diabetes, starvation or ingestion of ketogenic diet (Balasse and Fery, 1989; Cahill GF Jr, 2006; Girard et al., 1992; Hegardt, 1999; Satapati et al., 2012; Sengupta et al., 2010). In the fetus, methylation of 5� flanking region of Hmgcs2 gene inversely correlates with its transcription, and is partially reversed after birth (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983). Similarly, hepatic Bdh1 exhibits a developmental expression pattern, increasing from birth to weaning, and is also induced by ketogenic diet in a fibroblast growth factor (FGF)-21-dependent manner (Badman et al., 2007; Zhang et al., 1989). Ketogenesis in mammals is highly responsive to both insulin and glucagon, being suppressed and stimulated, respectively (McGarry and Foster, 1977). Insulin suppresses adipose tissue lipolysis, thus depriving ketogenesis of its substrate, while glucagon increases ketogenic flux through a direct effect on the liver (Hegardt, 1999). Hmgcs2 transcription is stimulated by forkhead transcriptional factor FOXA2, which is inhibited via insulin-phosphatidylinositol-3-kinase/Akt, and is induced by glucagon-cAMP-p300 signaling (Arias et al., 1995; Hegardt, 1999; Quant et al., 1990; Thumelin et al., 1993; von Meyenn et al., 2013; Wolfrum et al., 2004; Wolfrum et al., 2003). PPAR? (Rodriguez et al., 1994) together with its target, FGF21 (Badman et al., 2007) also induce Hmgcs2 transcription in the liver during starvation or administration of ketogenic diet (Badman et al., 2007; Inagaki et al., 2007). Induction of PPAR? may occur before the transition from fetal to neonatal physiology, while FGF21 activation may be favored in the early neonatal period via ?OHB-mediated inhibition of histone deacetylase (HDAC)-3 (Rando et al., 2016). mTORC1 (mammalian target of rapamycin complex 1) dependent inhibition of PPAR? transcriptional activity is also a key regulator of Hmgcs2 gene expression (Sengupta et al., 2010), and liver PER2, a master circadian oscillator, indirectly regulates Hmgcs2 expression (Chavan et al., 2016). Recent observations indicate that extrahepatic tumor-induced interleukin-6 impairs ketogenesis via PPAR? suppression (Flint et al., 2016). Despite these observations, it is important to note that physiological shifts in Hmgcs2 gene expression have not been mechanistically linked to HMGCS2 protein abundance or to variations of ketogenic rate.
HMGCS2 enzyme activity is regulated through multiple PTMs. HMGCS2 serine phosphorylation enhanced its activity in vitro (Grimsrud et al., 2012). HMGCS2 activity is allosterically inhibited by succinyl-CoA and lysine residue succinylation (Arias et al., 1995; Hegardt, 1999; Lowe and Tubbs, 1985; Quant et al., 1990; Rardin et al., 2013; Reed et al., 1975; Thumelin et al., 1993). Succinylation of HMGCS2, HMGCL, and BDH1 lysine residues in hepatic mitochondria are targets of the NAD+ dependent deacylase sirtuin 5 (SIRT5) (Rardin et al., 2013). HMGCS2 activity is also enhanced by SIRT3 lysine deacetylation, and it is possible that crosstalk between acetylation and succinylation regulates HMGCS2 activity (Rardin et al., 2013; Shimazu et al., 2013). Despite the ability of these PTMs to regulate HMGCS2 Km and Vmax, fluctuations of these PTMs have not yet been carefully mapped and have not been confirmed as mechanistic drivers of ketogenesis in vivo.
SCOT is expressed in all mammalian cells that harbor mitochondria, except those of hepatocytes. The importance of SCOT activity and ketolysis was demonstrated in SCOT-KO mice, which exhibited uniform lethality due to hyperketonemic hypoglycemia within 48h after birth (Cotter et al., 2011). Tissue-specific loss of SCOT in neurons or skeletal myocytes induces metabolic abnormalities during starvation but is not lethal (Cotter et al., 2013b). In humans, SCOT deficiency presents early in life with severe ketoacidosis, causing lethargy, vomiting, and coma (Berry et al., 2001; Fukao et al., 2000; Kassovska-Bratinova et al., 1996; Niezen-Koning et al., 1997; Saudubray et al., 1987; Snyderman et al., 1998; Tildon and Cornblath, 1972). Relatively little is known at the cellular level about SCOT gene and protein expression regulators. Oxct1 mRNA expression and SCOT protein and activity are diminished in ketotic states, possibly through PPAR-dependent mechanisms (Fenselau and Wallis, 1974; Fenselau and Wallis, 1976; Grinblat et al., 1986; Okuda et al., 1991; Turko et al., 2001; Wentz et al., 2010). In diabetic ketoacidosis, the mismatch between hepatic ketogenesis and extrahepatic oxidation becomes exacerbated by impairment of SCOT activity. Overexpression of insulin-independent glucose transporter (GLUT1/SLC2A1) in cardiomyocytes also inhibits Oxct1 gene expression and downregulates ketones terminal oxidation in a non-ketotic state (Yan et al., 2009). In liver, Oxct1 mRNA abundance is suppressed by microRNA-122 and histone methylation H3K27me3 that are evident during the transition from fetal to the neonatal period (Thorrez et al., 2011). However, suppression of hepatic Oxct1 expression in the postnatal period is primarily attributable to the evacuation of Oxct1-expressing hematopoietic progenitors from the liver, rather than a loss of previously existing Oxct1 expression in terminally differentiated hepatocytes. In fact, expression of Oxct1 mRNA and SCOT protein in differentiated hepatocytes are extremely low (Orii et al., 2008).
SCOT is also regulated by PTMs. The enzyme is hyper-acetylated in brains of SIRT3 KO mice, which also exhibit diminished AcAc dependent acetyl-CoA production (Dittenhafer-Reed et al., 2015). Non-enzymatic nitration of tyrosine residues of SCOT also attenuates its activity, which has been reported in hearts of various diabetic mice models (Marcondes et al., 2001; Turko et al., 2001; Wang et al., 2010a). In contrast, tryptophan residue nitration augments SCOT activity (Br�g�re et al., 2010; Rebrin et al., 2007). Molecular mechanisms of residue-specific nitration or de-nitration designed to modulate SCOT activity may exist and require elucidation.
Controversies in Extrahepatic Ketogenesis
In mammals the primary ketogenic organ is liver, and only hepatocytes and gut epithelial cells abundantly express the mitochondrial isoform of HMGCS2 (Cotter et al., 2013a; Cotter et al., 2014; McGarry and Foster, 1980; Robinson and Williamson, 1980). Anaerobic bacterial fermentation of complex polysaccharides yields butyrate, which is absorbed by colonocytes in mammalians for terminal oxidation or ketogenesis (Cherbuy et al., 1995), which may play a role in colonocyte differentiation (Wang et al., 2016). Excluding gut epithelial cells and hepatocytes, HMGCS2 is nearly absent in almost all other mammalian cells, but the prospect of extrahepatic ketogenesis has been raised in tumor cells, astrocytes of the central nervous system, the kidney, pancreatic ? cells, retinal pigment epithelium (RPE), and even in skeletal muscle (Adijanto et al., 2014; Avogaro et al., 1992; El Azzouny et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Le Foll et al., 2014; Nonaka et al., 2016; Takagi et al., 2016a; Thevenet et al., 2016; Zhang et al., 2011). Ectopic HMGCS2 has been observed in tissues that lack net ketogenic capacity (Cook et al., 2016; Wentz et al., 2010), and HMGCS2 exhibits prospective ketogenesis-independent �moonlighting� activities, including within the cell nucleus (Chen et al., 2016; Kostiuk et al., 2010; Meertens et al., 1998).
Any extrahepatic tissue that oxidizes ketone bodies also has the potential to accumulate ketone bodies via HMGCS2 independent mechanisms (Fig. 2A). However, there is no extrahepatic tissue in which a steady state ketone body concentration exceeds that in the circulation (Cotter et al., 2011; Cotter et al., 2013b; Harrison and Long, 1940), underscoring that ketone bodies are transported down a concentration gradient via MCT1/2-dependent mechanisms. One mechanism of apparent extrahepatic ketogenesis may actually reflect relative impairment of ketone oxidation. Additional potential explanations fall within the realm of ketone body formation. First, de novo ketogenesis may occur via reversible enzymatic activity of thiolase and SCOT (Weidemann and Krebs, 1969). When the concentration of acetyl-CoA is relatively high, reactions normally responsible for AcAc oxidation operate in the reverse direction (GOLDMAN, 1954). A second mechanism occurs when ?-oxidation-derived intermediates accumulate due to a TCA cycle bottleneck, AcAc-CoA is converted to l-?OHB-CoA through a reaction catalyzed by mitochondrial 3-hydroxyacyl-CoA dehydrogenase, and further by 3-hydroxybutyryl CoA deacylase to l-?OHB, which is indistinguishable by mass spectrometry or resonance spectroscopy from the physiological enantiomer d-?OHB (Reed and Ozand, 1980). l-?OHB can be chromatographically or enzymatically distinguished from d-?OHB, and is present in extrahepatic tissues, but not in liver or blood (Hsu et al., 2011). Hepatic ketogenesis produces only d-?OHB, the only enantiomer that is a BDH substrate (Ito et al., 1984; Lincoln et al., 1987; Reed and Ozand, 1980; Scofield et al., 1982; Scofield et al., 1982). A third HMGCS2-independent mechanism generates d-?OHB through amino acid catabolism, particularly that of leucine and lysine. A fourth mechanism is only apparent because it is due to a labeling artifact and is thus termed pseudoketogenesis. This phenomenon is attributable to the reversibility of the SCOT and thiolase reactions, and can cause overestimation of ketone body turnover due to the isotopic dilution of ketone body tracer in extrahepatic tissue (Des Rosiers et al., 1990; Fink et al., 1988). Nonetheless, pseudoketogenesis may be negligible in most contexts (Bailey et al., 1990; Keller et al., 1978). A schematic (Fig. 2A) indicates a useful approach to apply while considering elevated tissue steady state concentration of ketones.
� Kidney has recently received attention as a potentially ketogenic organ. In the vast majority of states, the kidney is a net consumer of liver-derived ketone bodies, excreting or reabsorbing ketone bodies from the bloodstream, and kidney is generally not a net ketone body generator or concentrator (Robinson and Williamson, 1980). The authors of a classical study concluded that minimal renal ketogenesis quantified in an artificial experimental system was not physiologically relevant (Weidemann and Krebs, 1969). Recently, renal ketogenesis has been inferred in diabetic and autophagy deficient mouse models, but it is more likely that multi-organ shifts in metabolic homeostasis alter integrative ketone metabolism through inputs on multiple organs (Takagi et al., 2016a; Takagi et al., 2016b; Zhang et al., 2011). One recent publication suggested renal ketogenesis as a protective mechanism against ischemia-reperfusion injury in the kidney (Tran et al., 2016). Absolute steady state concentrations of ?OHB from extracts of mice renal tissue were reported at ~4�12 mM. To test whether this was tenable, we quantified ?OHB concentrations in renal extracts from fed and 24h fasted mice. Serum ?OHB concentrations increased from ~100 �M to 2 mM with 24h fasting (Fig. 2B), while renal steady state ?OHB concentrations approximate 100 �M in the fed state, and only 1 mM in the 24h fasted state (Fig. 2C�E), observations that are consistent with concentrations quantified over 45 years ago (Hems and Brosnan, 1970). It remains possible that in ketotic states, liver-derived ketone bodies could be renoprotective, but evidence for renal ketogenesis requires further substantiation. Compelling evidence that supports true extrahepatic ketogenesis was presented in RPE (Adijanto et al., 2014). This intriguing metabolic transformation was suggested to potentially allow RPE-derived ketones to flow to photoreceptor or M�ller glia cells, which could aid in the regeneration of photoreceptor outer segment.
?OHB as a Signaling Mediator
Although they are energetically rich, ketone bodies exert provocative �non-canonical� signaling roles in cellular homeostasis (Fig. 3) (Newman and Verdin, 2014; Rojas-Morales et al., 2016). For example, ?OHB inhibits Class I HDACs, which increases histone acetylation and thereby induces the expression of genes that curtail oxidative stress (Shimazu et al., 2013). ?OHB itself is a histone covalent modifier at lysine residues in livers of fasted or streptozotocin induced diabetic mice (Xie et al., 2016) (also see below, The integration of ketone body metabolism, post-translational modification, and cell physiology, and Ketone bodies, oxidative stress, and neuroprotection).
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?OHB is also an effector via G-protein coupled receptors. Through unclear molecular mechanisms, it suppresses sympathetic nervous system activity and reduces total energy expenditure and heart rate by inhibiting short chain fatty acid signaling through G protein coupled receptor 41 (GPR41) (Kimura et al., 2011). One of the most studied signaling effects of ?OHB proceeds through GPR109A (also known as HCAR2), a member of the hydrocarboxylic acid GPCR sub-family expressed in adipose tissues (white and brown) (Tunaru et al., 2003), and in immune cells (Ahmed et al., 2009). ?OHB is the only known endogenous ligand of GPR109A receptor (EC50 ~770 �M) activated by d-?OHB, l-?OHB, and butyrate, but not AcAc (Taggart et al., 2005). The high concentration threshold for GPR109A activation is achieved through adherence to a ketogenic diet, starvation, or during ketoacidosis, leading to inhibition of adipose tissue lipolysis. The anti-lipolytic effect of GPR109A proceeds through inhibition of adenylyl cyclase and decreased cAMP, inhibiting hormone sensitive triglyceride lipase (Ahmed et al., 2009; Tunaru et al., 2003). This creates a negative feedback loop in which ketosis places a modulatory brake on ketogenesis by diminishing the release of non-esterified fatty acids from adipocytes (Ahmed et al., 2009; Taggart et al., 2005), an effect that can be counterbalanced by the sympathetic drive that stimulates lipolysis. Niacin (vitamin B3, nicotinic acid) is a potent (EC50 ~ 0.1 �M) ligand for GRP109A, effectively employed for decades for dyslipidemias (Benyo et al., 2005; Benyo et al., 2006; Fabbrini et al., 2010a; Lukasova et al., 2011; Tunaru et al., 2003). While niacin enhances reverse cholesterol transport in macrophages and reduces atherosclerotic lesions (Lukasova et al., 2011), the effects of ?OHB on atherosclerotic lesions remain unknown. Although GPR109A receptor exerts protective roles, and intriguing connections exist between ketogenic diet use in stroke and neurodegenerative diseases (Fu et al., 2015; Rahman et al., 2014), a protective role of ?OHB via GPR109A has not been demonstrated in vivo.
Finally, ?OHB may influence appetite and satiety. A meta-analysis of studies that measured the effects of ketogenic and very low energy diets concluded that participants consuming these diets exhibit higher satiety, compared to control diets (Gibson et al., 2015). However, a plausible explanation for this effect is the additional metabolic or hormonal elements that might modulate appetite. For example, mice maintained on a rodent ketogenic diet exhibited increased energy expenditure compared to chow control-fed mice, despite similar caloric intake, and circulating leptin or genes of peptides regulating feeding behavior were not changed (Kennedy et al., 2007). Among proposed mechanisms that suggest appetite suppression by ?OHB includes both signaling and oxidation (Laeger et al., 2010). Hepatocyte specific deletion of circadian rhythm gene (Per2)�and chromatin immunoprecipitation studies revealed that PER2 directly activates the Cpt1a gene, and indirectly regulates Hmgcs2, leading to impaired ketosis in Per2 knockout mice (Chavan et al., 2016). These mice exhibited impaired food anticipation, which was partially restored by systemic ?OHB administration. Future studies will be needed to confirm the central nervous system as a direct ?OHB target, and whether ketone oxidation is required for the observed effects, or whether another signaling mechanism is involved. Other investigators have invoked the possibility of local astrocyte-derived ketogenesis within the ventromedial hypothalamus as a regulator of food intake, but these preliminary observations also will benefit from genetic and flux-based assessments (Le Foll et al., 2014). The relationship between ketosis and nutrient deprivation remains of interest because hunger and satiety are important elements in failed weight loss attempts.
Integration of Ketone Body Metabolism, Post-Translational Modification, and Cell Physiology
Ketone bodies contribute to compartmentalized pools of acetyl-CoA, a key intermediate that exhibits prominent roles in cellular metabolism (Pietrocola et al., 2015). One role of acetyl-CoA is to serve as a substrate for acetylation, an enzymatically-catalyzed histone covalent modification (Choudhary et al., 2014; Dutta et al., 2016; Fan et al., 2015; Menzies et al., 2016). A large number of dynamically acetylated mitochondrial proteins, many of which may occur through non-enzymatic mechanisms, have also emerged from computational proteomics studies (Dittenhafer-Reed et al., 2015; Hebert et al., 2013; Rardin et al., 2013; Shimazu et al., 2010). Lysine deacetylases use a zinc cofactor (e.g., nucleocytosolic HDACs) or NAD+ as co-substrate (sirtuins, SIRTs) (Choudhary et al., 2014; Menzies et al., 2016). The acetylproteome serves as both sensor and effector of the total cellular acetyl-CoA pool, as physiological and genetic manipulations each result in non-enzymatic global variations of acetylation (Weinert et al., 2014). As intracellular metabolites serve as modulators of lysine residue acetylation, it is important to consider the role of ketone bodies, whose abundance is highly dynamic.
?OHB is an epigenetic modifier through at least two mechanisms. Increased ?OHB levels induced by fasting, caloric restriction, direct administration or prolonged exercise provoke HDAC inhibition or histone acetyltransferase activation (Marosi et al., 2016; Sleiman et al., 2016) or to oxidative stress (Shimazu et al., 2013). ?OHB inhibition of HDAC3 could regulate newborn metabolic physiology (Rando et al., 2016). Independently, ?OHB itself directly modifies histone lysine residues (Xie et al., 2016). Prolonged fasting, or steptozotocin-induced diabetic ketoacidosis increased histone ?-hydroxybutyrylation. Although the number of lysine ?-hydroxybutyrylation and acetylation sites was comparable, stoichiometrically greater histone ?-hydroxybutyrylation than acetylation was observed. Distinct genes were impacted by histone lysine ?-hydroxybutyrylation, versus acetylation or methylation, suggesting distinct cellular functions. Whether ?-hydroxybutyrylation is spontaneous or enzymatic is not known, but expands the range of mechanisms through ketone bodies dynamically influence transcription.
Essential cell reprogramming events during caloric restriction and nutrient deprivation may be mediated in SIRT3- and SIRT5-dependent mitochondrial deacetylation and desuccinylation, respectively, regulating ketogenic and ketolytic proteins at post-translational level in liver and extrahepatic tissues (Dittenhafer-Reed et al., 2015; Hebert et al., 2013; Rardin et al., 2013; Shimazu et al., 2010). Even though stoichiometric comparison of occupied sites does not necessarily link directly to shifts in metabolic flux, mitochondrial acetylation is dynamic and may be driven by acetyl-CoA concentration or mitochondrial pH, rather than enzymatic acetyltransferases (Wagner and Payne, 2013). That SIRT3 and SIRT5 modulate activities of ketone body metabolizing enzymes provokes the question of the reciprocal role of ketones in sculpting the acetylproteome, succinylproteome, and other dynamic cellular targets. Indeed, as variations of ketogenesis reflect NAD+ concentrations, ketone production and abundance could regulate sirtuin activity, thereby influencing total acetyl-CoA/succinyl-CoA pools, the acylproteome, and thus mitochondrial and cell physiology. ?-hydroxybutyrylation of enzyme lysine residues could add another layer to cellular reprogramming. In extrahepatic tissues, ketone body oxidation may stimulate analogous changes in cell homeostasis. While compartmentation of acetyl-CoA pools is highly regulated and coordinates a broad spectrum of cellular changes, the ability of ketone bodies to directly shape both mitochondrial and cytoplasmic acetyl-CoA concentrations requires elucidation (Chen et al., 2012; Corbet et al., 2016; Pougovkina et al., 2014; Schwer et al., 2009; Wellen and Thompson, 2012). Because acetyl-CoA concentrations are tightly regulated, and acetyl-CoA is membrane impermeant, it is crucial to consider the driver mechanisms coordinating acetyl-CoA homeostasis, including the rates of production and terminal oxidation in the TCA cycle, conversion into ketone bodies, mitochondrial efflux via carnitine acetyltransferase (CrAT), or acetyl-CoA export to cytosol after conversion to citrate and release by ATP citrate lyase (ACLY). The key roles of these latter mechanisms in cell acetylproteome and homeostasis require matched understanding of the roles of ketogenesis and ketone oxidation (Das et al., 2015; McDonnell et al., 2016; Moussaieff et al., 2015; Overmyer et al., 2015; Seiler et al., 2014; Seiler et al., 2015; Wellen et al., 2009; Wellen and Thompson, 2012). Convergent technologies in metabolomics and acylproteomics in the setting of genetically manipulated models will be required to specify targets and outcomes.
Anti- and Pro-Inflammatory Responses to Ketone Bodies
Ketosis and ketone bodies modulate inflammation and immune cell function, but varied and even discrepant mechanisms have been proposed. Prolonged nutrient deprivation reduces inflammation (Youm et al., 2015), but the chronic ketosis of type 1 diabetes is a pro-inflammatory state (Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Kurepa et al., 2012). Mechanism-based signaling roles for ?OHB in inflammation emerge because many immune system cells, including macrophages or monocytes, abundantly express GPR109A. While ?OHB exerts a predominantly anti-inflammatory response (Fu et al., 2014; Gambhir et al., 2012; Rahman et al., 2014; Youm et al., 2015), high concentrations of ketone bodies, particularly AcAc, may trigger a pro-inflammatory response (Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Kurepa et al., 2012).
Anti-inflammatory roles of GPR109A ligands in atherosclerosis, obesity, inflammatory bowel disease, neurological disease, and cancer have been reviewed (Graff et al., 2016). GPR109A expression is augmented in RPE cells of diabetic models, human diabetic patients (Gambhir et al., 2012), and in microglia during neurodegeneration (Fu et al., 2014). Anti-inflammatory effects of ?OHB are enhanced by GPR109A overexpression in RPE cells, and abrogated by pharmacological inhibition or genetic knockout of GPR109A (Gambhir et al., 2012). ?OHB and exogenous nicotinic acid (Taggart et al., 2005), both confer anti-inflammatory effects in TNF? or LPS-induced inflammation by decreasing the levels of pro-inflammatory proteins (iNOS, COX-2), or secreted cytokines (TNF?, IL-1?, IL-6, CCL2/MCP-1), in part through inhibiting NF-?B translocation (Fu et al., 2014; Gambhir et al., 2012). ?OHB decreases ER stress and the NLRP3 inflammasome, activating the antioxidative stress response (Bae et al., 2016; Youm et al., 2015). However, in neurodegenerative inflammation, GPR109A-dependent ?OHB-mediated protection does not involve inflammatory mediators like MAPK pathway signaling (e.g., ERK, JNK, p38) (Fu et al., 2014), but may require COX-1-dependent PGD2 production (Rahman et al., 2014). It is intriguing that macrophage GPR109A is required to exert a neuroprotective effect in an ischemic stroke model (Rahman et al., 2014), but the ability of ?OHB to inhibit the NLRP3 inflammasome in bone marrow derived macrophages is GPR109A independent (Youm et al., 2015). Although most studies link ?OHB to anti-inflammatory effects, ?OHB may be pro-inflammatory and increase markers of lipid peroxidation in calf hepatocytes (Shi et al., 2014). Anti- versus pro-inflammatory effects of ?OHB may thus depend on cell type, ?OHB concentration, exposure duration, and the presence or absence of co-modulators.
Unlike ?OHB, AcAc may activate pro-inflammatory signaling. Elevated AcAc, especially with a high glucose concentration, intensifies endothelial cell injury through an NADPH oxidase/oxidative stress dependent mechanism (Kanikarla-Marie and Jain, 2015). High AcAc concentrations in umbilical cord of diabetic mothers were correlated with higher protein oxidation rate and MCP-1 concentration (Kurepa et al., 2012). High AcAc in diabetic patients was correlated with TNF? expression (Jain et al., 2002), and AcAc, but not ?OHB, induced TNF?, MCP-1 expression, ROS accumulation, and diminished cAMP level in U937 human monocyte cells (Jain et al., 2002; Kurepa et al., 2012).
Ketone body dependent signaling phenomena are frequently triggered only with high ketone body concentrations (> 5 mM), and in the case of many studies linking ketones to pro- or anti-inflammatory effects, through unclear mechanisms. In addition, due to the contradictory effects of ?OHB versus AcAc on inflammation, and the ability of AcAc/?OHB ratio to influence mitochondrial redox potential, the best experiments assessing the roles of ketone bodies on cellular phenotypes compare the effects of AcAc and ?OHB in varying ratios, and at varying cumulative concentrations [e.g., (Saito et al., 2016)]. Finally, AcAc can be purchased commercially only as a lithium salt or as an ethyl ester that requires base hydrolysis before use. Lithium cation independently induces signal transduction cascades (Manji et al., 1995), and AcAc anion is labile. Finally, studies using racemic d/l-?OHB can be confounded, as only the d-?OHB stereoisomer can be oxidized to AcAc, but d-?OHB and l-?OHB can each signal through GPR109A, inhibit the NLRP3 inflammasome, and serve as lipogenic substrates.
Ketone Bodies, Oxidative Stress, and Neuroprotection
Oxidative stress is typically defined as a state in which ROS are presented in excess, due to excessive production and/or impaired elimination. Antioxidant and oxidative stress mitigating roles of ketone bodies have been widely described both in vitro and in vivo, particularly in the context of neuroprotection. As most neurons do not effectively generate high-energy phosphates from fatty acids�but do oxidize ketone bodies when carbohydrates are in short supply, neuroprotective effects of ketone bodies are especially important (Cahill GF Jr, 2006; Edmond et al., 1987; Yang et al., 1987). In oxidative stress models, BDH1 induction and SCOT suppression suggest that ketone body metabolism can be reprogrammed to sustain diverse cell signaling, redox potential, or metabolic requirements (Nagao et al., 2016; Tieu et al., 2003).
Ketone bodies decrease the grades of cellular damage, injury, death and lower apoptosis in neurons and cardiomyocytes (Haces et al., 2008; Maalouf et al., 2007; Nagao et al., 2016; Tieu et al., 2003). Invoked mechanisms are varied and not always linearly related to concentration. Low millimolar concentrations of (d or l)-?OHB scavenge ROS (hydroxyl anion), while AcAc scavenges numerous ROS species, but only at concentrations that exceed the physiological range (IC50 20�67 mM) (Haces et al., 2008). Conversely, a beneficial influence over the electron transport chain�s redox potential is a mechanism commonly linked to d-?OHB. While all three ketone bodies (d/l-?OHB and AcAc) reduced neuronal cell death and ROS accumulation triggered by chemical inhibition of glycolysis, only d-?OHB and AcAc prevented neuronal ATP decline. Conversely, in a hypoglycemic in vivo model, (d or l)-?OHB, but not AcAc prevented hippocampal lipid peroxidation (Haces et al., 2008; Maalouf et al., 2007; Marosi et al., 2016; Murphy, 2009; Tieu et al., 2003). In vivo studies of mice fed a ketogenic diet (87% kcal fat and 13% protein) exhibited neuroanatomical variation of antioxidant capacity (Ziegler et al., 2003), where the most profound changes were observed in hippocampus, with increase glutathione peroxidase and total antioxidant capacities.
Ketogenic diet, ketone esters (also see Therapeutic use of ketogenic diet and exogenous ketone bodies), or ?OHB administration exert neuroprotection in models of ischemic stroke (Rahman et al., 2014); Parkinson�s disease (Tieu et al., 2003); central nervous system oxygen toxicity seizure (D’Agostino et al., 2013); epileptic spasms (Yum et al., 2015); mitochondrial encephalomyopathy, lactic acidosis and stroke-like (MELAS) episodes syndrome (Frey et al., 2016) and Alzheimer�s disease (Cunnane and Crawford, 2003; Yin et al., 2016). Conversely, a recent report demonstrated histopathological evidence of neurodegenerative progression by a ketogenic diet in a transgenic mouse model of abnormal mitochondrial DNA repair, despite increases in mitochondrial biogenesis and antioxidant signatures (Lauritzen et al., 2016). Other conflicting reports suggest that exposure to high ketone body concentrations elicits oxidative stress. High ?OHB or AcAc doses induced nitric oxide secretion, lipid peroxidation, reduced expression of SOD, glutathione peroxidase and catalase in calf hepatocytes, while in rat hepatocytes the MAPK pathway induction was attributed to AcAc but not ?OHB (Abdelmegeed et al., 2004; Shi et al., 2014; Shi et al., 2016).
Taken together, most reports link ?OHB to attenuation of oxidative stress, as its administration inhibits ROS/superoxide production, prevents lipid peroxidation and protein oxidation, increases antioxidant protein levels, and improves mitochondrial respiration and ATP production (Abdelmegeed et al., 2004; Haces et al., 2008; Jain et al., 1998; Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Maalouf et al., 2007; Maalouf and Rho, 2008; Marosi et al., 2016; Tieu et al., 2003; Yin et al., 2016; Ziegler et al., 2003). While AcAc has been more directly correlated than ?OHB with the induction of oxidative stress, these effects are not always easily dissected from prospective pro-inflammatory responses (Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Kanikarla-Marie and Jain, 2016). Moreover, it is critical to consider that the apparent antioxidative benefit conferred by pleiotropic ketogenic diets may not be transduced by ketone bodies themselves, and neuroprotection conferred by ketone bodies may not entirely be attributable to oxidative stress. For example during glucose deprivation, in a model of glucose deprivation in cortical neurons, ?OHB stimulated autophagic flux and prevented autophagosome accumulation, which was associated with decreased neuronal death (Camberos-Luna et al., 2016). d-?OHB induces also the canonical antioxidant proteins FOXO3a, SOD, MnSOD, and catalase, prospectively through HDAC inhibition (Nagao et al., 2016; Shimazu et al., 2013).
Non-Alcoholic Fatty Liver Disease (NAFLD) and Ketone Body Metabolism
Obesity-associated NAFLD and nonalcoholic steatohepatitis (NASH) are the most common causes of liver disease in Western countries (Rinella and Sanyal, 2016), and NASH-induced liver failure is one of the most common reasons for liver transplantation. While excess storage of triacylglycerols in hepatocytes >5% of liver weight (NAFL) alone does not cause degenerative liver function, the progression to NAFLD in humans correlates with systemic insulin resistance and increased risk of type 2 diabetes, and may contribute to the pathogenesis of cardiovascular disease and chronic kidney disease (Fabbrini et al., 2009; Targher et al., 2010; Targher and Byrne, 2013). The pathogenic mechanisms of NAFLD and NASH are incompletely understood but include abnormalities of hepatocyte metabolism, hepatocyte autophagy and endoplasmic reticulum stress, hepatic immune cell function, adipose tissue inflammation, and systemic inflammatory mediators (Fabbrini et al., 2009; Masuoka and Chalasani, 2013; Targher et al., 2010; Yang et al., 2010). Perturbations of carbohydrate, lipid, and amino acid metabolism occur in and contribute to obesity, diabetes, and NAFLD in humans and in model organisms [reviewed in (Farese et al., 2012; Lin and Accili, 2011; Newgard, 2012; Samuel and Shulman, 2012; Sun and Lazar, 2013)]. While hepatocyte abnormalities in cytoplasmic lipid metabolism are commonly observed in NAFLD (Fabbrini et al., 2010b), the role of mitochondrial metabolism, which governs oxidative disposal of fats is less clear in NAFLD pathogenesis. Abnormalities of mitochondrial metabolism occur in and contribute to NAFLD/NASH pathogenesis (Hyotylainen et al., 2016; Serviddio et al., 2011; Serviddio et al., 2008; Wei et al., 2008). There is general (Felig et al., 1974; Iozzo et al., 2010; Koliaki et al., 2015; Satapati et al., 2015; Satapati et al., 2012; Sunny et al., 2011) but not uniform (Koliaki and Roden, 2013; Perry et al., 2016; Rector et al., 2010) consensus that, prior to the development of bona fide NASH, hepatic mitochondrial oxidation, and in particular fat oxidation, is augmented in obesity, systemic insulin resistance, and NAFLD. It is likely that as NAFLD progresses, oxidative capacity heterogenity, even among individual mitochondria, emerges, and ultimately oxidative function becomes impaired (Koliaki et al., 2015; Rector et al., 2010; Satapati et al., 2008; Satapati et al., 2012).
Ketogenesis is often used as a proxy for hepatic fat oxidation. Impairments of ketogenesis emerge as NAFLD progresses in animal models, and likely in humans. Through incompletely defined mechanisms, hyperinsulinemia suppresses ketogenesis, possibly contributing to hypoketonemia compared to lean controls (Bergman et al., 2007; Bickerton et al., 2008; Satapati et al., 2012; Soeters et al., 2009; Sunny et al., 2011; Vice et al., 2005). Nonetheless, the ability of circulating ketone body concentrations to predict NAFLD is controversial (M�nnist� et al., 2015; Sanyal et al., 2001). Robust quantitative magnetic resonance spectroscopic methods in animal models revealed increased ketone turnover rate with moderate insulin resistance, but decreased rates were evident with more severe insulin resistance (Satapati et al., 2012; Sunny et al., 2010). In obese humans with fatty liver, ketogenic rate is normal (Bickerton et al., 2008; Sunny et al., 2011), and hence, the rates of ketogenesis are diminished relative to the increased fatty acid load within hepatocytes. Consequently, ?-oxidation-derived acetyl-CoA may be directed to terminal oxidation in the TCA cycle, increasing terminal oxidation, phosphoenolpyruvate-driven gluconeogenesis via anaplerosis/cataplerosis, and oxidative stress. Acetyl-CoA also possibly undergoes export from mitochondria as citrate, a precursor substrate for lipogenesis (Fig. 4) (Satapati et al., 2015; Satapati et al., 2012; Solinas et al., 2015). While ketogenesis becomes less responsive to insulin or fasting with prolonged obesity (Satapati et al., 2012), the underlying mechanisms and downstream consequences of this remain incompletely understood. Recent evidence indicates that mTORC1 suppresses ketogenesis in a manner that may be downstream of insulin signaling (Kucejova et al., 2016), which is concordant with the observations that mTORC1 inhibits PPAR?-mediated Hmgcs2 induction (Sengupta et al., 2010) (also see Regulation of HMGCS2 and SCOT/OXCT1).
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Preliminary observations from our group suggest adverse hepatic consequences of ketogenic insufficiency (Cotter et al., 2014). To test the hypothesis that impaired ketogenesis, even in carbohydrate-replete and thus �non-ketogenic� states, contributes to abnormal glucose metabolism and provokes steatohepatitis, we generated a mouse model of marked ketogenic insufficiency by administration of antisense oligonucleotides (ASO) targeted to Hmgcs2. Loss of HMGCS2 in standard low-fat chow-fed adult mice caused mild hyperglycemia and markedly increased production of hundreds of hepatic metabolites, a suite of which strongly suggested lipogenesis activation. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation. These findings support the central hypotheses that (i) ketogenesis is not a passive overflow pathway but rather a dynamic node in hepatic and integrated physiological homeostasis, and (ii) prudent ketogenic augmentation to mitigate NAFLD/NASH and disordered hepatic glucose metabolism is worthy of exploration.
How might impaired ketogenesis contribute to hepatic injury and altered glucose homeostasis? The first consideration is whether the culprit is deficiency of ketogenic flux, or ketones themselves. A recent report suggests that ketone bodies may mitigate oxidative stress-induced hepatic injury in response to n-3 polyunsaturated fatty acids (Pawlak et al., 2015). Recall that due to lack of SCOT expression in hepatocytes, ketone bodies are not oxidized, but they can contribute to lipogenesis, and serve a variety of signaling roles independent of their oxidation (also see Non-oxidative metabolic fates of ketone bodies and ?OHB as a signaling mediator). It is also possible that hepatocyte-derived ketone bodies may serve as a signal and/or metabolite for neighboring cell types within the hepatic acinus, including stellate cells and Kupffer cell macrophages. While the limited literature available suggests that macrophages are unable to oxidize ketone bodies, this has only been measured using classical methodologies, and only in peritoneal macrophages (Newsholme et al., 1986; Newsholme et al., 1987), indicating that a re-assessment is appropriate given abundant SCOT expression in bone marrow-derived macrophages (Youm et al., 2015).
Hepatocyte ketogenic flux may also be cytoprotective. While salutary mechanisms may not depend on ketogenesis per se, low carbohydrate ketogenic diets have been associated with amelioration of NAFLD (Browning et al., 2011; Foster et al., 2010; Kani et al., 2014; Schugar and Crawford, 2012). Our observations indicate that hepatocyte ketogenesis may feedback and regulate TCA cycle flux, anaplerotic flux, phosphoenolpyruvate-derived gluconeogenesis (Cotter et al., 2014), and even glycogen turnover. Ketogenic impairment directs acetyl-CoA to increase TCA flux, which in liver has been linked to increased ROS-mediated injury (Satapati et al., 2015; Satapati et al., 2012); forces diversion of carbon into de novo synthesized lipid species that could prove cytotoxic; and prevents NADH re-oxidation to NAD+ (Cotter et al., 2014) (Fig. 4). Taken together, future experiments are required to address mechanisms through which relative ketogenic insufficiency may become maladaptive, contribute to hyperglycemia, provoke steatohepatitis, and whether these mechanisms are operant in human NAFLD/NASH. As epidemiological evidence suggests impaired ketogenesis during the progression of steatohepatitis (Embade et al., 2016; Marinou et al., 2011; M�nnist� et al., 2015; Pramfalk et al., 2015; Safaei et al., 2016) therapies that increase hepatic ketogenesis could prove salutary (Degirolamo et al., 2016; Honda et al., 2016).
Ketone Bodies and Heart Failure (HF)
With a metabolic rate exceeding 400 kcal/kg/day, and a turnover of 6�35 kg ATP/day, the heart is the organ with the highest energy expenditure and oxidative demand (Ashrafian et al., 2007; Wang et al., 2010b). The vast majority of myocardial energy turnover resides within mitochondria, and 70% of this supply originates from FAO. The heart is omnivorous and flexible under normal conditions, but the pathologically remodeling heart (e.g., due to hypertension or myocardial infarction) and the diabetic heart each become metabolically inflexible (Balasse and Fery, 1989; BING, 1954; Fukao et al., 2004; Lopaschuk et al., 2010; Taegtmeyer et al., 1980; Taegtmeyer et al., 2002; Young et al., 2002). Indeed, genetically programmed abnormalities of cardiac fuel metabolism in mouse models provoke cardiomyopathy (Carley et al., 2014; Neubauer, 2007). Under physiological conditions normal hearts oxidize ketone bodies in proportion to their delivery, at the expense of fatty acid and glucose oxidation, and myocardium is the highest ketone body consumer per unit mass (BING, 1954; Crawford et al., 2009; GARLAND et al., 1962; Hasselbaink et al., 2003; Jeffrey et al., 1995; Pelletier et al., 2007; Tardif et al., 2001; Yan et al., 2009). Compared to fatty acid oxidation, ketone bodies are more energetically efficient, yielding more energy available for ATP synthesis per molecule of oxygen invested (P/O ratio) (Kashiwaya et al., 2010; Sato et al., 1995; Veech, 2004). Ketone body oxidation also yields potentially higher energy than FAO, keeping ubiquinone oxidized, which raises redox span in the electron transport chain and makes more energy available to synthetize ATP (Sato et al., 1995; Veech, 2004). Oxidation of ketone bodies may also curtail ROS production, and thus oxidative stress (Veech, 2004).
Preliminary interventional and observational studies indicate a potential salutary role of ketone bodies in the heart. In the experimental ischemia/reperfusion injury context, ketone bodies conferred potential cardioprotective effects (Al-Zaid et al., 2007; Wang et al., 2008), possibly due to the increase mitochondrial abundance in heart or up-regulation of crucial oxidative phosphorylation mediators (Snorek et al., 2012; Zou et al., 2002). Recent studies indicate that ketone body utilization is increased in failing hearts of mice (Aubert et al., 2016) and humans (Bedi et al., 2016), supporting prior observations in humans (BING, 1954; Fukao et al., 2000; Janardhan et al., 2011; Longo et al., 2004; Rudolph and Schinz, 1973; Tildon and Cornblath, 1972). Circulating ketone body concentrations are increased in heart failure patients, in direct proportion to filling pressures, observations whose mechanism and significance remains unknown (Kupari et al., 1995; Lommi et al., 1996; Lommi et al., 1997; Neely et al., 1972), but mice with selective SCOT deficiency in cardiomyocytes exhibit accelerated pathological ventricular remodeling and ROS signatures in response to surgically induced pressure overload injury (Schugar et al., 2014).
Recent intriguing observations in diabetes therapy have revealed a potential link between myocardial ketone metabolism and pathological ventricular remodeling (Fig. 5). Inhibition of the renal proximal tubular sodium/glucose co-transporter 2 (SGLT2i) increases circulating ketone body concentrations in humans (Ferrannini et al., 2016a; Inagaki et al., 2015) and mice (Suzuki et al., 2014) via increased hepatic ketogenesis (Ferrannini et al., 2014; Ferrannini et al., 2016a; Katz and Leiter, 2015; Mudaliar et al., 2015). Strikingly, at least one of these agents decreased HF hospitalization (e.g., as revealed by the EMPA-REG OUTCOME trial), and improved cardiovascular mortality (Fitchett et al., 2016; Sonesson et al., 2016; Wu et al., 2016a; Zinman et al., 2015). While the driver mechanisms behind beneficial HF outcomes to linked SGLT2i remain actively debated, the survival benefit is likely multifactorial, prospectively including ketosis but also salutary effects on weight, blood pressure, glucose and uric acid levels, arterial stiffness, the sympathetic nervous system, osmotic diuresis/reduced plasma volume, and increased hematocrit (Raz and Cahn, 2016; Vallon and Thomson, 2016). Taken together, the notion that therapeutically increasing ketonemia either in HF patients, or those at high risk to develop HF, remains controversial but is under active investigation in pre-clinical and clinical studies (Ferrannini et al., 2016b; Kolwicz et al., 2016; Lopaschuk and Verma, 2016; Mudaliar et al., 2016; Taegtmeyer, 2016).
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Ketone Bodies in Cancer Biology
Connections between ketone bodies and cancer are rapidly emerging, but studies in both animal models and humans have yielded diverse conclusions. Because ketone metabolism is dynamic and nutrient state responsive, it is enticing to pursue biological connections to cancer because of the potential for precision-guided nutritional therapies. Cancer cells undergo metabolic reprogramming in order to maintain rapid cell proliferation and growth (DeNicola and Cantley, 2015; Pavlova and Thompson, 2016). The classical Warburg effect in cancer cell metabolism arises from the dominant role of glycolysis and lactic acid fermentation to transfer energy and compensate for lower dependence on oxidative phosphorylation and limited mitochondrial respiration (De Feyter et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Poff et al., 2014; Shukla et al., 2014). Glucose carbon is primarily directed through glycolysis, the pentose phosphate pathway, and lipogenesis, which together provide intermediates necessary for tumor biomass expansion (Grabacka et al., 2016; Shukla et al., 2014; Yoshii et al., 2015). Adaptation of cancer cells to glucose deprivation occurs through the ability to exploit alternative fuel sources, including acetate, glutamine, and aspartate (Jaworski et al., 2016; Sullivan et al., 2015). For example, restricted access to pyruvate reveals the ability of cancer cells to convert glutamine into acetyl-CoA by carboxylation, maintaining both energetic and anabolic needs (Yang et al., 2014). An interesting adaptation of cancer cells is the utilization of acetate as a fuel (Comerford et al., 2014; Jaworski et al., 2016; Mashimo et al., 2014; Wright and Simone, 2016; Yoshii et al., 2015). Acetate is also a substrate for lipogenesis, which is critical for tumor cell proliferation, and gain of this lipogenic conduit is associated with shorter patient survival and greater tumor burden (Comerford et al., 2014; Mashimo et al., 2014; Yoshii et al., 2015).
Non-cancer cells easily shift their energy source from glucose to ketone bodies during glucose deprivation. This plasticity may be more variable among cancer cell types, but in vivo implanted brain tumors oxidized [2,4-13C2]-?OHB to a similar degree as surrounding brain tissue (De Feyter et al., 2016). �Reverse Warburg effect� or �two compartment tumor metabolism� models hypothesize that cancer cells induce ?OHB production in adjacent fibroblasts, furnishing the tumor cell�s energy needs (Bonuccelli et al., 2010; Martinez-Outschoorn et al., 2012). In liver, a shift in hepatocytes from ketogenesis to ketone oxidation in hepatocellular carcinoma (hepatoma) cells is consistent with activation of BDH1 and SCOT activities observed in two hepatoma cell lines (Zhang et al., 1989). Indeed, hepatoma cells express OXCT1 and BDH1 and oxidize ketones, but only when serum starved (Huang et al., 2016). Alternatively, tumor cell ketogenesis has also been proposed. Dynamic shifts in ketogenic gene expression are exhibited during cancerous transformation of colonic epithelium, a cell type that normally expresses HMGCS2, and a recent report suggested that HMGCS2 may be a prognostic marker of poor prognosis in colorectal and squamous cell carcinomas (Camarero et al., 2006; Chen et al., 2016). Whether this association requires or involves ketogenesis, or a moonlighting function of HMGCS2, remains to be determined. Conversely, apparent ?OHB production by melanoma and glioblastoma cells, stimulated by the PPAR? agonist fenofibrate, was associated with growth arrest (Grabacka et al., 2016). Further studies are required to characterize roles of HMGCS2/SCOT expression, ketogenesis, and ketone oxidation in cancer cells.
Beyond the realm of fuel metabolism, ketones have recently been implicated in cancer cell biology via a signaling mechanism. Analysis of BRAF-V600E+ melanoma indicated OCT1-dependent induction of HMGCL in an oncogenic BRAF-dependent manner (Kang et al., 2015). HMGCL augmentation was correlated with higher cellular AcAc concentration, which in turn enhanced BRAFV600E-MEK1 interaction, amplifying MEK-ERK signaling in a feed-forward loop that drives tumor cell proliferation and growth. These observations raise the intriguing question of prospective extrahepatic ketogenesis that then supports a signaling mechanism (also see ?OHB as a signaling mediator and Controversies in extrahepatic ketogenesis). It is also important to consider independent effects of AcAc, d-?OHB, and l-?OHB on cancer metabolism, and when considering HMGCL, leucine catabolism may also be deranged.
The effects of ketogenic diets (also see Therapeutic use of ketogenic diet and exogenous ketone bodies) in cancer animal models are varied (De Feyter et al., 2016; Klement et al., 2016; Meidenbauer et al., 2015; Poff et al., 2014; Seyfried et al., 2011; Shukla et al., 2014). While epidemiological associations among obesity, cancer, and ketogenic diets are debated (Liskiewicz et al., 2016; Wright and Simone, 2016), a meta-analysis using ketogenic diets in animal models and in human studies suggested a salutary impact on survival, with benefits prospectively linked to the magnitude of ketosis, time of diet initiation, and tumor location (Klement et al., 2016; Woolf et al., 2016). Treatment of pancreatic cancer cells with ketone bodies (d-?OHB or AcAc) inhibited growth, proliferation and glycolysis, and a ketogenic diet (81% kcal fat, 18% protein, 1% carbohydrate) reduced in vivo tumor weight, glycemia, and increased muscle and body weight in animals with implanted cancer (Shukla et al., 2014). Similar results were observed using a metastatic glioblastoma cell model in mice that received ketone supplementation in the diet (Poff et al., 2014). Conversely, a ketogenic diet (91% kcal fat, 9% protein) increased circulating ?OHB concentration and diminished glycemia�but had no impact on either tumor volume or survival duration in glioma-bearing rats (De Feyter et al., 2016). A glucose ketone index has been proposed as a clinical indicator that improves metabolic management of ketogenic diet-induced brain cancer therapy in humans and mice (Meidenbauer et al., 2015). Taken together, roles of ketone body metabolism and ketone bodies in cancer biology are tantalizing because they each pose tractable therapeutic options, but fundamental aspects remain to be elucidated, with clear influences emerging from a matrix of variables, including (i) differences between exogenous ketone bodies versus ketogenic diet, (ii) cancer cell type, genomic polymorphisms, grade, and stage; and (iii) timing and duration of exposure to the ketotic state.
Ketogenesis is created by ketone bodies through the breakdown of fatty acids and ketogenic amino acids. This biochemical process provides energy to various organs, specifically the brain, under circumstances of fasting as a response to an unavailability of blood glucose. Ketone bodies are mainly produced in the mitochondria of liver cells. While other cells are capable of carrying out ketogenesis, they are not as effective at doing so as liver cells. Because ketogenesis occurs in the mitochondria, its processes are regulated independently. Dr. Alex Jimenez D.C., C.C.S.T. Insight
Therapeutic Application of Ketogenic Diet and Exogenous Ketone Bodies
The applications of ketogenic diets and ketone bodies as therapeutic tools have also arisen in non-cancerous contexts including obesity and NAFLD/NASH (Browning et al., 2011; Foster et al., 2010; Schugar and Crawford, 2012); heart failure (Huynh, 2016; Kolwicz et al., 2016; Taegtmeyer, 2016); neurological and neurodegenerative disease (Martin et al., 2016; McNally and Hartman, 2012; Rho, 2015; Rogawski et al., 2016; Yang and Cheng, 2010; Yao et al., 2011); inborn errors of metabolism (Scholl-B�rgi et al, 2015); and exercise performance (Cox et al., 2016). The efficacy of ketogenic diets has been especially appreciated in therapy of epileptic seizure, particularly in drug-resistant patients. Most studies have evaluated ketogenic diets in pediatric patients, and reveal up to a ~50% reduction in seizure frequency after 3 months, with improved effectiveness in select syndromes (Wu et al., 2016b). The experience is more limited in adult epilepsy, but a similar reduction is evident, with better response in symptomatic generalized epilepsy patients (Nei et al., 2014). Underlying anti-convulsant mechanisms remain unclear, although postulated hypotheses include reduced glucose utilization/glycolysis, reprogrammed glutamate transport, indirect impact on ATP-sensitive potassium channel or adenosine A1 receptor, alteration of sodium channel isoform expression, or effects on circulating hormones including leptin (Lambrechts et al., 2016; Lin et al., 2017; Lutas and Yellen, 2013). It remains unclear whether the anti-convulsant effect is primarily attributable to ketone bodies, or due to the cascade metabolic consequences of low carbohydrate diets. Nonetheless, ketone esters (see below) appear to elevate the seizure threshold in animal models of provoked seizures (Ciarlone et al., 2016; D’Agostino et al., 2013; Viggiano et al., 2015).
Atkins-style and ketogenic, low carbohydrate diets are often deemed unpleasant, and can cause constipation, hyperuricemia, hypocalcemia, hypomagnesemia, lead to nephrolithiasis, ketoacidosis, cause hyperglycemia, and raise circulating cholesterol and free fatty acid concentrations (Bisschop et al., 2001; Kossoff and Hartman, 2012; Kwiterovich et al., 2003; Suzuki et al., 2002). For these reasons, long-term adherence poses challenges. Rodent studies commonly use a distinctive macronutrient distribution (94% kcal fat, 1% kcal carbohydrate, 5% kcal protein, Bio-Serv F3666), which provokes a robust ketosis. However, increasing the protein content, even to 10% kcal substantially diminishes the ketosis, and 5% kcal protein restriction confers confounding metabolic and physiological effects. This diet formulation is also choline depleted, another variable that influences susceptibility to liver injury, and even ketogenesis (Garbow et al., 2011; Jornayvaz et al., 2010; Kennedy et al., 2007; Pissios et al., 2013; Schugar et al., 2013). Effects of long-term consumption of ketogenic diets in mice remain incompletely defined, but recent studies in mice revealed normal survival and the absence of liver injury markers in mice on ketogenic diets over their lifespan, although amino acid metabolism, energy expenditure, and insulin signaling were markedly reprogrammed (Douris et al., 2015).
Mechanisms increasing ketosis through mechanisms alternative to ketogenic diets include the use of ingestible ketone body precursors. Administration of exogenous ketone bodies could create a unique physiological state not encountered in normal physiology, because circulating glucose and insulin concentrations are relatively normal, while cells might spare glucose uptake and utilization. Ketone bodies themselves have short half-lives, and ingestion or infusion of sodium ?OHB salt to achieve therapeutic ketosis provokes an untoward sodium load. R/S-1,3-butanediol is a non-toxic dialcohol that is readily oxidized in the liver to yield d/l-?OHB (Desrochers et al., 1992). In distinct experimental contexts, this dose has been administered daily to mice or rats for as long as seven weeks, yielding circulating ?OHB concentrations of up to 5 mM within 2 h of administration, which is stable for at least an additional 3h (D’Agostino et al., 2013). Partial suppression of food intake has been observed in rodents given R/S-1,3-butanediol (Carpenter and Grossman, 1983). In addition, three chemically distinct ketone esters (KEs), (i) monoester of R-1,3-butanediol and d-?OHB (R-3-hydroxybutyl R-?OHB); (ii) glyceryl-tris-?OHB; and (iii) R,S-1,3-butanediol acetoacetate diester, have also been extensively studied (Brunengraber, 1997; Clarke et al., 2012a; Clarke et al., 2012b; Desrochers et al., 1995a; Desrochers et al., 1995b; Kashiwaya et al., 2010). An inherent advantage of the former is that 2 moles of physiological d-?OHB are produced per mole of KE, following esterase hydrolysis in the intestine or liver. Safety, pharmacokinetics, and tolerance have been most extensively studied in humans ingesting R-3-hydroxybutyl R-?OHB, at doses up to 714 mg/kg, yielding circulating d-?OHB concentrations up to 6 mM (Clarke et al., 2012a; Cox et al., 2016; Kemper et al., 2015; Shivva et al., 2016). In rodents, this KE decreases caloric intake and plasma total cholesterol, stimulates brown adipose tissue, and improves insulin resistance (Kashiwaya et al., 2010; Kemper et al., 2015; Veech, 2013). Recent findings indicate that during exercise in trained athletes, R-3-hydroxybutyl R-?OHB ingestion decreased skeletal muscle glycolysis and plasma lactate concentrations, increased intramuscular triacylglycerol oxidation, and preserved muscle glycogen content, even when co-ingested carbohydrate stimulated insulin secretion (Cox et al., 2016). Further development of these intriguing results is required, because the improvement in endurance exercise performance was predominantly driven by a robust response to the KE in 2/8 subjects. Nonetheless, these results do support classical studies that indicate a preference for ketone oxidation over other substrates (GARLAND et al., 1962; Hasselbaink et al., 2003; Stanley et al., 2003; Valente-Silva et al., 2015), including during exercise, and that trained athletes may be more primed to utilize ketones (Johnson et al., 1969a; Johnson and Walton, 1972; Winder et al., 1974; Winder et al., 1975). Finally, the mechanisms that might support improved exercise performance following equal caloric intake (differentially distributed among macronutrients) and equal oxygen consumption rates remain to be determined. Clues may emerge from animal studies, as temporary exposure to R-3-hydroxybutyl R-?OHB in rats was associated with increased treadmill time, improved cognitive function, and an apparent energetic benefit in ex vivo perfused hearts (Murray et al., 2016).
Future Perspective
Once largely stigmatized as an overflow pathway capable of accumulating toxic emissions from fat combustion in carbohydrate restricted states (the �ketotoxic� paradigm), recent observations support the notion that ketone body metabolism serves salutary roles even in carbohydrate-laden states, opening a �ketohormetic� hypothesis. While the facile nutritional and pharmacological approaches to manipulate ketone metabolism make it an attractive therapeutic target, aggressively posed but prudent experiments remain in both the basic and translational research laboratories. Unmet needs have emerged in the domains of defining the role of leveraging ketone metabolism in heart failure, obesity, NAFLD/NASH, type 2 diabetes, and cancer. The scope and impact of ‘non-canonical� signaling roles of ketone bodies, including regulation of PTMs that likely feed back and forward into metabolic and signaling pathways, require deeper exploration. Finally, extrahepatic ketogenesis could open intriguing paracrine and autocrine signaling mechanisms and opportunities to influence co-metabolism within the nervous system and tumors to achieve therapeutic ends.
In conclusion, ketone bodies are created by the liver in order to be used as an energy source when there is not enough glucose readily available in the human body. Ketogenesis occurs when there are low glucose levels in the blood, particularly after other cellular carbohydrate stores have been exhausted. The purpose of the article above was to discuss the multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
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