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Ketogenic Diet *

Introduction: Despite continuous advances in the medical world, obesity continues to remain a major worldwide health hazard with adult mortality as high as 2.8 million per year. The majority of chronic diseases like diabetes, hypertension, and heart disease are largely related to obesity which is usually a product of unhealthy lifestyle and poor dietary habits. Appropriately tailored diet regimens for weight reduction can help manage the obesity epidemic to some extent. One diet regimen that has proven to be very effective for rapid weight loss is a very-low-carbohydrate and high-fat ketogenic diet. *

Function A ketogenic diet primarily consists of high-fats, moderate-proteins, and very-low-carbohydrates. The dietary macronutrients are divided into approximately 55% to 60% fat, 30% to 35% protein and 5% to 10% carbohydrates. Specifically, in a 2000 kcal per day diet, carbohydrates amount up to 20 to 50 g per day.

History and Origin: Russel Wilder first used the ketogenic diet to treat epilepsy in 1921. He also coined the term “ketogenic diet.” For almost a decade, the ketogenic diet enjoyed a place in the medical world as a therapeutic diet for pediatric epilepsy and was widely used until its popularity ceased with the introduction of antiepileptic agents. The resurgence of the ketogenic diet as a rapid weight loss formula is a relatively new concept the has shown to be quite effective, at least in the short run.

Physiology and Biochemistry: Basically, carbohydrates are the primary source of energy production in body tissues. When the body is deprived of carbohydrates due to reducing intake to less than 50g per day, insulin secretion is significantly reduced and the body enters a catabolic state. Glycogen stores deplete, forcing the body to go through certain metabolic changes. Two metabolic processes come into action when there is low carbohydrate availability in body tissues: gluconeogenesis and ketogenesis. *

Gluconeogenesis is the endogenous production of glucose in the body, especially in the liver primarily from lactic acid, glycerol, and the amino acids alanine and glutamine. When glucose availability drops further, the endogenous production of glucose is not able to keep up with the needs of the body and ketogenesis begins in order to provide an alternate source of energy in the form of ketone bodies. Ketone bodies replace glucose as a primary source of energy. During ketogenesis due to low blood glucose feedback, stimulus for insulin secretion is also low, which sharply reduces the stimulus for fat and glucose storage. Other hormonal changes may contribute to the increased breakdown of fats that result in fatty acids. Fatty acids are metabolized to acetoacetate which is later converted to beta-hydroxybutyrate and acetone. These are the basic ketone bodies that accumulate in the body as a ketogenic diet is sustained. This metabolic state is referred to as “nutritional ketosis.” As long as the body is deprived of carbohydrates, metabolism remains in the ketotic state. The nutritional ketosis state is considered quite safe, as ketone bodies are produced in small concentrations without any alterations in blood pH. It greatly differs from ketoacidosis, a life-threatening condition where ketone bodies are produced in extremely larger concentrations, altering blood ph to acidotic a state.

Ketone bodies synthesized in the body can be easily utilized for energy production by heart, muscle tissue, and the kidneys. Ketone bodies also can cross the blood-brain barrier to provide an alternative source of energy to the brain. RBCs and the liver do not utilize ketones due to lack of mitochondria and enzyme diaphorase respectively. Ketone body production depends on several factors such as resting basal metabolic rate (BMR), body mass index (BMI), and body fat percentage. Ketone bodies produce more adenosine triphosphate in comparison to glucose, sometimes aptly called a “super fuel.” One hundred grams of acetoacetate generates 9400 grams of ATP, and 100 g of beta-hydroxybutyrate yields 10,500 grams of ATP; whereas, 100 grams of glucose produces only 8,700 grams of ATP. This allows the body to maintain efficient fuel production even during a caloric deficit. Ketone bodies also decrease free radical damage and enhance antioxidant capacity.

Issues of Concern

Adverse Effects: The short-term effects (up to 2 years) of the ketogenic diet are well reported and established. However, the long-term health implications are not well known due to limited literature. *

The most common and relatively minor short-term side effects of ketogenic diet include a collection of symptoms like nausea, vomiting, headache, fatigue, dizziness, insomnia, difficulty in exercise tolerance, and constipation, sometimes referred to as keto flu. These symptoms resolve in a few days to few weeks. Ensuring adequate fluid and electrolyte intake can help counter some of these symptoms. Long-term adverse effects include hepatic steatosis, hypoproteinemia, kidney stones, and vitamin and mineral deficiencies.

Cautions and Contraindications: People suffering from diabetes and taking insulin or oral hypoglycemic agents suffer severe hypoglycemia if the medications are not appropriately adjusted before initiating this diet. The ketogenic diet is contraindicated in patients with pancreatitis, liver failure, disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyltransferase deficiency, carnitine translocase deficiency, porphyrias, or pyruvate kinase deficiency. People on a ketogenic diet rarely can have a false positive breath alcohol test. Due to ketonemia, acetone in the body can sometimes be reduced to isopropanol by hepatic alcohol dehydrogenase which can give a false positive alcohol breath test result.

Clinical Significance: The popular belief that high-fat diets cause obesity and several other diseases such as coronary heart disease, diabetes, and cancer has not been observed in recent epidemiological studies. Studies carried out in animals that were fed high-fat diets did not show a specific causal relationship between dietary fat and obesity. On the contrary, very-low-carbohydrate and high-fat diets such as the ketogenic diet have shown to beneficial to weight loss.

Evidence Behind The Ketogenic Diet: In relation to overall caloric intake, carbohydrates comprise around 55% of the typical American diet, ranging from 200 to 350 g/day. The vast potential of refined carbohydrates to cause harmful effects were relatively neglected until recently. A greater intake of sugar-laden food is associated with a 44% increased prevalence of metabolic syndrome and obesity and a 26% increase in the risk of developing diabetes mellitus. In a 2012 study of all cardiometabolic deaths (heart disease, stroke, and type 2 diabetes) in the United States, an estimated 45.4% were associated with suboptimal intakes of 10 dietary factors. The largest estimated mortality was associated with high sodium intake (9.5%), followed by low intake of nuts and seeds (8.5%), high intake of processed meats (8.2%), low intake of omega-3 fats (7.8%), low intake of vegetables 7.6%), low intake of fruits (7.5%), and high intake of artificially sweetened beverages (7.4%). The lowest estimated mortality was associated with low polyunsaturated fats (2.3%) and unprocessed red meats (0.4%). In addition to this direct harm, excess consumption of low-quality carbohydrates may displace and leave no room in the diet for healthier foods like nuts, unprocessed grains, fruits, and vegetables.

A recent systemic review and meta-analysis of randomized controlled trials comparing the long-term effects (greater than 1 year) of dietary interventions on weight loss showed no sound evidence for recommending low-fat diets. In fact, low-carbohydrate diets led to significantly greater weight loss compared to low-fat interventions. It was observed that a carbohydrate-restricted diet is better than a low-fat diet for retaining an individual’s BMR. In other words, the quality of calories consumed may affect the number of calories burned. BMR dropped by more than 400 kcal/day on a low-fat diet when compared to a very low-carb diet.

A well-formulated ketogenic diet, besides limiting carbohydrates, also limits protein intake moderately to less than 1g/lb body weight, unless individuals are performing heavy exercise involving weight training when the protein intake can be increased to 1.5g/lb body weight. This is to prevent the endogenous production of glucose in the body via gluconeogenesis. However, it does not restrict fat or overall daily calories. People on a ketogenic diet initially experience rapid weight loss up to 10 lbs in 2 weeks or less. This diet has a diuretic effect, and some early weight loss is due to water weight loss followed by a fat loss. Interestingly with this diet plan, lean body muscle is largely spared. As a nutritional ketosis state sustains, hunger pangs subside, and an overall reduction in caloric intake helps to further weight loss.

Other Issues: Long-term compliance is low and can be a big issue with a ketogenic diet, but this is the case with any lifestyle change. Even though the ketogenic diet is significantly superior in the induction of weight loss in otherwise healthy patients with obesity and the induced weight loss is rapid, intense, and sustained until at least 2 year, the understanding of the clinical impacts, safety, tolerability, efficacy, duration of treatment, and prognosis after discontinuation of the diet is challenging and requires further studies to understand the disease-specific mechanisms.

A ketogenic diet may be followed for a minimum of 2 to 3 weeks up to 6 to 12 months. Close monitoring of renal functions while on a ketogenic diet is imperative, and the transition from a ketogenic diet to a standard diet should be gradual and well controlled.

Enhancing Healthcare Team Outcomes: To counter the obesity epidemic, some healthcare workers do recommend the ketogenic diet. However, the primary care provider, nurse practitioner, dietitian and internist need to be aware of a few facts.

Overweight individuals with metabolic syndrome, insulin resistance, and type 2 diabetes are likely to see improvements in the clinical markers of disease risk with a well-formulated very-low-carbohydrate diet. Glucose control improves due to less glucose introduction and improved insulin sensitivity. In addition to reducing weight, especially truncal obesity and insulin resistance, low-carb diets also may help improve blood pressure, blood glucose regulation, triglycerides, and HDL cholesterol levels. However, LDL cholesterol may increase on this diet.

Also, in various studies, the ketogenic diet has shown promising results in a variety of neurological disorders, like epilepsy, dementia, ALS, traumatic brain injury, acne, cancers, and metabolic disorders.

Due to the complexity of the mechanism and lack of long-term studies, a general recommendation of the ketogenic diet for prevention of type 2 diabetes mellitus or cardiovascular disease may seem premature but is, however, not farfetched for primary weight loss.

While in the short term the ketogenic diet may help one lose weight, this is not sustained over the long run. In addition, countless studies show that the diet is associated with many complications that often lead to emergency room visits and admissions for dehydration, electrolyte disturbances, and hypoglycemia. *

Source: Wajeed Masood, Pavan Annamaraju, Kalyan R. Uppaluri. “Ketogenic Diet” StatPearls (2020) June.

Calcium Citrate

Ketotic Hypercalcemia: A Case Series and Description of a Novel Entity *

Context: The ketogenic diet is increasingly used in refractory epilepsy and is associated with clinically significant effects on bone and mineral metabolism. Although hypercalciuria and loss of bone mineral density are common in patients on the ketogenic diet, hypercalcemia has not previously been described.

Objective: The aim of the study was to describe three children who developed hypercalcemia while on the ketogenic diet.

Design: A retrospective chart review of three children on the ketogenic with severe hypercalcemia was conducted.

Results: We describe three children on the ketogenic diet for refractory seizures who presented with hypercalcemia. Case 1 was a 5.5-year-old male with an undiagnosed, rapidly progressive seizure disorder associated with developmental regression. Case 2 was a 2.5-year-old male with a chromosomal deletion of 2q24.3, and case 3 was a 4.6-year-old male with cerebral cortex dysplasia. Patients had been on a ketogenic diet for 6 to 12 months before presentation. Daily intake of calcium and vitamin D was not excessive, and all three patients were not acidotic because they were taking supplemental bicarbonate. Each child had elevated serum levels of calcium and normal serum phosphate levels, moderately elevated urinary calcium excretion, and low levels of serum alkaline phosphatase, PTH, and 1,25-dihydroxyvitamin D. All patients responded to calcitonin.

Conclusions: Hypercalcemia is an uncommon complication of the ketogenic diet, and these children may represent the severe end of a clinical spectrum of disordered mineral metabolism. The mechanism for hypercalcemia is unknown but is consistent with excess bone resorption and impaired calcium excretion.

Source: Colin Patrick Hawkes, Michael A. Levine. “Ketotic Hypercalcemia: A Case Series and Description of a Novel Entity” The Journal of Clinical Endocrinology & Metabolism, (2014): Volume 99, Issue 5, 1531–1536.

Bone loss and biomechanical reduction of appendicular and axial bones under ketogenic diet in rats *


A ketogenic diet (KD) is composed of low-carbohydrate, high-fat and adequate levels of protein. It has been used for decades as a method to treat pediatric refractory epilepsy. However, recently, its side effects on the bones have received increasing attention. In order to comprehensively evaluate the effect of KD on the microstructures and mechanical properties of the skeleton, 14 male Sprague-Dawley rats were equally divided into two groups and fed with a KD (ratio of fat to carbohydrate and protein, 3:1) or a standard diet for 12 weeks. Body weight, as well as blood ketone and glucose levels, were monitored during the experiment. Bone morphometric analyses via micro-computerized tomography were performed on cortical and trabecular bone at the middle L4 vertebral body, the proximal humerus and tibia. The compressive stiffness and strength of scanned skeletal areas were calculated using micro-finite element analysis. The KD led to higher ketone levels and lower glucose levels, with reduced body weight and total bone mineral density (TBMD). After 12 weeks, the diet reduced the bone volume fraction, the trabecular number of cancellous bone, cortical thickness, total cross-sectional area inside the periosteal envelope and the bone area of cortical bone in the tibia and humerus, while increasing trabecular separation. However, KD may not affect the L4 vertebral body. The serum calcium or phosphate concentrations in the blood remained unchanged. In addition, bone stiffness and strength were clearly decreased by the KD, and significantly correlated with the BMD and bone area at all scanned sites. In conclusion, KD led to significant bone loss and reduced biomechanical function in appendicular bones, with a lesser impact on axial bones.

Source: Jianyang Ding, Xiaolin Xu, Xiuhua Wu, Zucheng Huang, Ganggang Kong, Junhao Liu, Zhiping Huang, Qi Liu, Rong Li,Zhou Yang, Yapu Liu, Qingan Zhu. “Bone loss and biomechanical reduction of appendicular and axial bones under ketogenic diet in rats” Experimental and Therapeutic Science (2019): 17(4): 2503–2510.

Apple Cider Vinegar

Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects *

Objective: To investigate the potential of acetic acid supplementation as a means of lowering the glycaemic index (GI) of a bread meal, and to evaluate the possible dose–response effect on postprandial glycaemia, insulinaemia and satiety.

Subjects and setting: In all, 12 healthy volunteers participated and the tests were performed at Applied Nutrition and Food Chemistry, Lund University, Sweden.

Intervention: Three levels of vinegar (18, 23 and 28 mmol acetic acid) were served with a portion of white wheat bread containing 50 g available carbohydrates as breakfast in randomized order after an overnight fast. Bread served without vinegar was used as a reference meal. Blood samples were taken during 120 min for analysis of glucose and insulin. Satiety was measured with a subjective rating scale.

Results: A significant dose–response relation was seen at 30 min for blood glucose and serum insulin responses; the higher the acetic acid level, the lower the metabolic responses. Furthermore, the rating of satiety was directly related to the acetic acid level. Compared with the reference meal, the highest level of vinegar significantly lowered the blood glucose response at 30 and 45 min, the insulin response at 15 and 30 min as well as increased the satiety score at 30, 90 and 120 min postprandially. The low and intermediate levels of vinegar also lowered the 30 min glucose and the 15 min insulin responses significantly compared with the reference meal. When GI and II (insulinaemic indices) were calculated using the 90 min incremental area, a significant lowering was found for the highest amount of acetic acid, although the corresponding values calculated at 120 min did not differ from the reference meal.

Conclusion: Supplementation of a meal based on white wheat bread with vinegar reduced postprandial responses of blood glucose and insulin, and increased the subjective rating of satiety. There was an inverse dose–response relation between the level of acetic acid and glucose and insulin responses and a linear dose–response relation between acetic acid and satiety rating. The results indicate an interesting potential of fermented and pickled products containing acetic acid.

Source: E Östman, Y Granfeldt, L Persson, I Björck. “Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects” European Journal of Clinical Nutrition (2005): volume 59, 983–988.

Vinegar Intake Reduces Body Weight, Body Fat Mass, and Serum Triglyceride Levels in Obese Japanese Subjects *

Acetic acid (AcOH), a main component of vinegar, recently was found to suppress body fat accumulation in animal studies. Hence we investigated the effects of vinegar intake on the reduction of body fat mass in obese Japanese in a double-blind trial. The subjects were randomly assigned to three groups of similar body weight, body mass index (BMI), and waist circum- ference. During the 12-week treatment period, the subjects in each group ingested 500ml daily of a beverage containing either 15 ml of vinegar (750 mg AcOH), 30 ml of vinegar (1,500 mg AcOH), or 0 ml of vinegar (0mg AcOH, placebo). Body weight, BMI, visceral fat area, waist circumference, and serum triglyceride levels were significantly lower in both vinegar intake groups than in the placebo group. In conclusion, daily intake of vinegar might be useful in the prevention of metabolic syndrome by reducing obesity.

Source: Tomoo KONDO, Mikiya KISHI, Takashi FUSHIMI, Shinobu UGAJIN & Takayuki KAGA “Vinegar Intake Reduces Body Weight, Body Fat Mass, and Serum Triglyceride Levels in Obese Japanese Subjects” Bioscience, Biotechnology, and Biochemistry (2009): 73:8, 1837-1843.

BHB – Beta-Hydroxybutyrate BHB Calcium/Magnesium/Sodium

Effect of a Sodium and Calcium DL-β-Hydroxybutyrate Salt in Healthy Adults *


Background: Ketone body therapy and supplementation are of high interest for several medical and nutritional fields. The intake of ketone bodies is often discussed in relation to rare metabolic diseases, such as multiple acyl-CoA dehydrogenase deficiency (MADD), that have no alternatives for treatment. Case reports showed positive results of therapy using ketone bodies. The number of ketone body salts offered on the wellness market is increasing steadily. More information on the kinetics of intake, safety, and tolerance of these products is needed.

Methods: In a one-dose kinetic study, six healthy subjects received an intervention (0.5 g/kg bw) using a commercially available ketone body supplement. The supplement contained a mixture of sodium and calcium D-/L-β-hydroxybutyrate (βHB) as well as food additives. The blood samples drawn in the study were tested for concentrations of D-βHB, glucose, and electrolytes, and blood gas analyses were done. Data on sensory evaluation and observed side effects of the supplement were collected. The product also went through chemical food analysis.

Results: The supplement led to a significant increase of D-βHB concentration in blood 2.5 and 3 h after oral intake (). The first significant effect was measured after 2 h with a mean value of 0.598 ± 0.300 mmol/L at the peak, which was recorded at 2.5 h. Changes in serum electrolytes and BGA were largely unremarkable. Taking the supplement was not without side effects. One subject dropped out due to gastrointestinal symptoms and two others reported similar but milder problems.

Conclusions: Intake of a combination of calcium and sodium D-/L-βHB salt shows a slow resorption with a moderate increase of D-βHB in serum levels. An influence of βHB salts on acid-base balance could not be excluded by this one-dose study. Excessive regular consumption without medical observation is not free of adverse effects. The tested product can therefore not be recommended unconditionally.

Source: Tobias Fischer, Ulrike Och, Ira Klawon, Tim Och, Marianne Grüneberg, Manfred Fobker, Ursula Bordewick-Dell, Thorsten Marquardt. “Effect of a Sodium and Calcium DL-β -Hydroxybutyrate Salt in Healthy Adults” Journal of Nutrition and Metabolism (2018): 9812806.

β-Hydroxybutyrate – A Signaling Metabolite *


Mammals have developed a variety of mechanisms for adapting to changes in the environment, particularly changes in food availability and nutrient stress. Many of these nutrient-responsive pathways have broader effects on health and are emerging as regulators of fundamental mechanisms of aging. Fasting and dietary restriction, for example, have long been the most consistently effective intervention to slow various effects of aging and prolong the life span of otherwise healthy mammals. It is increasingly understood that the effects of fasting involve the actions of specific molecular signaling pathways. Cellular energy metabolites act as key mediators of many of these pathways, linking the external environment to changes in cellular function (43). Nicotinamide adenine dinucleotide (NAD), for example, accepts high-energy electrons from reactions in the catabolism of glucose and fatty acids and transfers them to acceptor molecules to either produce ATP or perform energetically demanding metabolic reactions. However, in its oxidized form (NAD+), NAD is also a cofactor for sirtuin enzymes and poly-ADP-ribose polymerase (PARP), both of which consume NAD in the course of removing acyl groups from and adding poly-ADP to proteins, respectively. Sirtuins and PARP thereby regulate cellular functions ranging from gene expression and DNA damage repair to fatty acid metabolism (134). During times of fasting, or relative scarcity of cellular energy, more NAD is in the oxidized state, and sirtuins and PARP can be more active.

NAD+, a simple energy carrier, thereby acts as a fulcrum around which many cellular processes can be regulated in response to changes in the external environment. Such signaling metabolites include acetyl-CoA (coenzyme A), another carrier of high-energy bonds that is also substrate for a widely prevalent protein posttranslational modification (lysine acetylation), and S-adenosyl-methionine, which similarly is substrate for a common posttranslational modification of histones and other proteins (methylation) (43). Independent manipulation of these signaling molecules can recapitulate, or abrogate, some of the broader biological effects of environmental changes such as fasting or dietary restriction. For example, long-term dietary restriction can prevent the onset of common age-related hearing loss in C57BL/6 mice. However, dietary restriction in mice that carry a genetic knockout of the NAD-dependent sirtuin gene SIRT3 has no such beneficial effect (122). Inhibition of the TOR (target of rapamycin) signaling complex by rapamycin (46), activation of AMPK by metformin (81), or provision of NAD+ precursors (161) recapitulates some of the beneficial effects of dietary restriction on diseases of aging and longevity. Understanding the specific molecular actions of these signaling pathways and signaling metabolites that link changes in the environment to broad regulation of cellular functions will permit researchers to more precisely capture the therapeutic potential of metabolic or dietary changes to treat disease. It might also help explain the heterogeneous responses of individuals to such environmental changes, depending on their genetic or epigenetic capacity to generate and respond to these signaling metabolites.

Here, we review the signaling activities of the endogenous metabolite β-hydroxybutyrate (BHB). BHB is the most abundant ketone body in mammals. Ketone bodies are small molecules synthesized primarily in the liver from fats that circulate through the bloodstream during fasting, prolonged exercise, and when carbohydrates are restricted. They are taken up by tissues in need of energy, converted first to acetyl-CoA and then to ATP. Emerging evidence, however, shows that BHB not only is a passive carrier of energy but also has a variety of signaling functions both at the cell surface and intracellularly that can affect, for example, gene expression, lipid metabolism, neuronal function, and metabolic rate. Some of these effects are direct actions of BHB itself. Some are indirect effects governed by downstream metabolites into which BHB is converted, such as acetyl-CoA. We focus this review on BHB itself, referring to ketogenic diets only when necessary for translational context. Although ketogenic diets have been widely used both for research into the effects of ketone bodies and as therapeutics for conditions ranging from epilepsy to obesity, a ketogenic diet is a complex physiological state with many possible active components of which BHB is only one. Still, the signaling effects of BHB we summarize are likely relevant to the molecular mechanisms of interventions such as fasting, dietary restriction, and ketogenic diets. Altogether, these observations present a picture of a powerful molecule that offers both opportunities and cautions in its therapeutic application to common human diseases.

BHB: Structure And Metabolism

Ketone bodies are small, lipid-derived molecules that provide energy to tissues when glucose is scarce, such as during fasting or prolonged exercise. Over 80% of the human body’s stored energy resides in the fatty acids contained in adipose tissue (7). During fasting, after muscle and liver stores of glycogen are depleted, fatty acids are mobilized from adipocytes and transported to the liver for conversion to ketone bodies. Ketone bodies are then distributed via blood circulation to metabolically active tissues, such as muscle or brain, where they are metabolized into acetyl-CoA and eventually ATP (7). In humans, serum levels of BHB are usually in the low micromolar range but begin to rise to a few hundred micromolar after 12−-16 h of fasting, reaching 1−-2 mM after 2 days of fasting (13, 109) and 6−-8 mM with prolonged starvation (12). Similarly, serum levels of BHB can reach 1−-2 mM after 90 min of intense exercise (64). Consistent levels above 2 mM are also reached with a ketogenic diet that is almost devoid of carbohydrates (60). The term ketone bodies usually includes three molecules that are generated during ketogenesis: BHB, acetoacetate, and acetone. Most of the dynamic range in ketone body levels is in the form of BHB. When ketogenesis is activated, such as during fasting, blood levels of BHB rise much faster than either acetoacetate or acetone (74).

Regulation of Ketone Body Metabolism

The biochemistry of ketone body production and utilization is well understood and has been recently summarized both in the literature and in textbooks (e.g., 7, 66, 92) (Figure 1). Two points are particularly relevant to understanding the signaling activities of BHB. First, the same enzyme, β-hydroxybutyrate dehydrogenase (BDH1; EC, interconverts BHB and acetoacetate in both the final step of ketogenesis and the first step of BHB utilization. BDH1 imparts chirality to BHB, as described below. Second, regulation of BHB synthesis is controlled via two principal mechanisms: substrate availability in the form of fatty acids and expression and activity of the enzyme HMG-CoA synthase (HMGCS2; EC Ketogenesis occurs mostly in the liver (7), although expression of HMGCS2 may be sufficient to produce ketogenesis in other tissues (128, 160). Insulin and glucagon regulate ketogenesis primarily by modulating the availability of fatty acid substrates at the levels of mobilization from adipose tissue and importation into hepatic mitochondria (71). HMGCS2 gene expression is regulated by insulin/glucagon via acetylation and deacetylation of the FOXA2 transcription factor (144, 145, 136). FOXA2 deacetylation is controlled in part by the NAD-responsive enzyme SIRT1 (136). HMGCS2 gene expression is also regulated indirectly by the target of rapamycin complex mTORC1; mTORC1 inhibition is required for the activation of peroxisome proliferator-activated receptor alpha (PPARα) and fibroblast growth factor 21 (FGF21), both of which are required to induce ketogenesis (3, 4, 49, 117). The activity of HMGCS2 is regulated posttranslationally by succinylation and acetylation, regulated by the mitochondrial desuccinylase SIRT5 (104) and deacetylase SIRT3 (118), respectively. Altogether, this network of regulation centered on HMGCS2, involving substrate availability, transcriptional control, and posttranslational modification, lends tight temporal and spatial precision to BHB synthesis.

Neurotransmitter Synthesis

The potential mechanisms of action of ketogenic diets in treating epilepsy remain complex and controversial and have been the subject of several thorough reviews (47, 83, 156). One mechanism consistently proposed, however, involves how the downstream effects of BHB catabolism on the abundance or flux of other intermediate metabolites might alter the biosynthesis of the inhibitory neurotransmitter GABA.

The biosynthesis of GABA in inhibitory GABAergic neurons begins with the synthesis of glutamine in astrocytes. Glutamine is exported from astrocytes to neurons, where it undergoes conversion to glutamate and then decarboxylation to GABA. An alternative fate for glutamate in neurons is donation of its amino moiety to oxaloacetate, producing aspartate and α-ketoglutarate. Studies of isotopically labeled BHB show that it is used as a substrate for the synthesis of glutamine and other amino acids (158). Data from clinical studies of children on ketogenic diet for epilepsy show that cerebrospinal fluid GABA levels are higher on ketogenic diet, and the highest levels correlate with best seizure control (16).

BHB may affect GABA production via increased synthesis and/or pushing the fate of glutamate toward GABA and away from aspartate. Studies in synaptosomes show that BHB increases the content of glutamate and decreases that of aspartate (25). Studies of ketogenic diet in rodents similarly show that less glutamate is converted to aspartate (158). In cultured astrocytes, the presence of acetoacetate reduces the conversion of labeled glutamate to aspartate (157). Infusion of labeled BHB into rats fed a normal diet rapidly increases the levels of all components of this pathway (glutamine, glutamate, GABA, and aspartate) (113). Even when ketotic states are not associated with an increase in overall GABA levels, the proportion of glutamate shunted to GABA production is increased (84). The reason for this shunt may be the effect of BHB catabolism on TCA cycle intermediates. The relatively greater efficiency of BHB at generating acetyl-CoA compared with that of glucose, described above, increases the flux of acetyl-CoA through the TCA cycle. This increases the proportion of oxaloacetate required to condense with acetyl-CoA to permit its entry into the TCA cycle, reducing the availability of free oxaloacetate to participate in glutamate deamination to aspartate. By indirectly tying up oxaloacetate, BHB pushes the fate of glutamate toward GABA (156). Altogether, one effect of BHB catabolism, alone or as part of a ketogenic diet, appears to increase the capacity of GABAergic neurons to rapidly generate GABA from glutamate (156).

Although BHB is structurally reminiscent of GABA itself, evidence of a direct effect of BHB on activating GABA receptors is lacking. Neither BHB nor acetoacetate alters GABA currents in cultured rodent cortical neurons (22) or in rat hippocampal neurons (127). BHB did enhance the function of GABAA receptors expressed in Xenopus oocytes, but only modestly and at concentrations of 10 mM or higher (150), leaving the physiological significance of this effect unclear. However, GABOB (γ-amino-β-hydroxybutyric acid) is an endogenous agonist of GABA receptors that differs structurally from BHB only in the presence of the γ-amino moiety. It is biochemically plausible that BHB might be a direct substrate for GABOB synthesis, but no such aminotransferase is known to exist. Nor has any pathway for conversion of GABA to GABOB yet been identified in mammals. Of interest in consideration of BHB precursors as therapeutics, the enantiomer of GABOB that would be derived from S-BHB has the more potent antiepileptic affect and is a stronger GABAB receptor agonist (149).

BHB Signaling In Regulation Of Metabolism

The integration of the various direct and indirect signaling functions of BHB appears to broadly help the organism adapt to a fasting state. The transition to a fasting state is already under way when ketogenesis is activated in the liver. BHB production might further promote that transition in extrahepatic tissues while also fine-tuning the control of lipid and glucose metabolism.

The combinatorial effects of BHB on gene expression, described below, might be expected to generally facilitate the activation of new transcriptional programs. The enrichment of histone K(BHB) at genes activated by fasting suggests that this might be particularly important for activating fasting-related gene networks, although this could also reflect a nonspecific association with activated transcription.

Inhibition of class I HDACs by BHB could play a major role in metabolic reprogramming, according to studies of HDAC knockout mice and of HDAC inhibitors. HDAC3 regulates expression of gluconeogenic genes (86), and HDAC3 knockout mice have reduced fasting glucose and insulin levels (8, 26, 63). In fact, chronic treatment with the HDAC inhibitor butyrate essentially keeps mice metabolically normal on a high-fat diet, with lower glucose and insulin levels, better glucose tolerance, reduced weight gain, and improved respiratory efficiency (32). Butyrate also provides some of these benefits even to mice already obese from being fed a high-fat diet (32). Similarly, inhibition of class I HDACs, but not class II HDACs, increases mitochondrial biogenesis, improves insulin sensitivity, and increases metabolic rate and oxidative metabolism in a mouse diabetes model (31). The mechanism for these metabolic benefits of class I HDAC inhibition may be upregulation of PGC1α (Ppargc1a) in in a variety of tissues by relief of HDAC3-mediated transcriptional repression (31, 32). Transcription of Fgf21 is similarly upregulated via inhibition of HDAC3 by butyrate, activating ketogenesis in obese mice (72). Several single nucleotide polymorphisms in HDAC3 have been associated with an elevated risk of type 2 diabetes in a Chinese population (159).

Activation of HCAR2 reduces lipolysis in adipocytes; because the availability of fatty acids in the liver is a critical determinant of ketogenesis (and is strongly regulated by insulin), this may provide a self-feedback mechanism to limit the production of BHB. Why this mechanism is insufficient to prevent dysregulated BHB production in insulin-deficient states such as diabetic ketoacidosis, and whether it could be potentiated to treat such states, such as through HCAR2 agonists, is unclear.

HCAR2 was originally identified as a niacin receptor, spurring efforts to develop more specific agonists to capture the therapeutic benefits of niacin on cardiovascular risk or glycemic control that were thought to be due to HCAR2’s effects on the levels of free fatty acid in blood. An HCAR2 agonist, GSK256073, transiently reduces levels of free fatty acids in blood but has only a modest effect on glycemic control in type 2 diabetes mellitus (20). Two other HCAR2 agonists similarly lowered free fatty acids but without otherwise altering the lipid profile in humans, while niacin was found to produce beneficial changes to the lipid profile in Hcar2 knockout mice (69). Thus, the model that niacin (and by extension BHB) exerts beneficial effects on cardiovascular risk through activation of HCAR2 in adipose tissue is probably too simplistic. It may even be the case that other cell types such as macrophages might mediate the therapeutic effects of HCAR2 agonists (30).

Interpreting the metabolic effects of BHB mediated by FFAR3 depends on whether BHB acts as an agonist or antagonist, and in which contexts. Strong evidence suggests that BHB antagonizes FFAR3 to reduce sympathetic activity, resulting in reduced heart rate, body temperature, and metabolic rate. If BHB also antagonizes FFAR3 in other contexts, it could improve insulin secretion from pancreatic β islet cells and impair intestinal gluconeogenesis. Altogether, these findings suggest that BHB would improve glycemic control, though a decrease in metabolic rate could be obesogenic.

The important role of the NLRP3 inflammasome in regulating obesity-associated inflammation and metabolic dysfunction has been extensively reviewed (15, 45). Briefly, the NLRP3 inflammasome appears to mediate an inflammatory response to nutrient excess and mitochondrial dysfunction. Mice deficient in NLRP3 are grossly normal when fed chow but are protected from obesity and insulin resistance when fed a high-fat diet. One proposed mechanism is through a reduction in inflammasome-induced IL-1β, which otherwise inhibits insulin signaling in adipocytes and hepatocytes while inducing pancreatic β-cell dysfunction. While NLRP3 may have an important homeostatic role in the response to day-to-day nutrient fluctuations, its chronic activation by nutrient excess may contribute to the development of metabolic disease—and inhibition of the NLRP3 inflammasome by BHB might ameliorate these maladaptations.

BHB In The Brain: Epilepsy, Dementia, And Cognition

The ketogenic diet has been clinically used for decades to treat epilepsy and currently has a wide range of therapeutic applications, mostly in childhood epilepsies (143). Despite this extensive clinical history, the mechanism of action of the ketogenic diet remains controversial (107). In fact, whether BHB itself is necessary or even active in the therapeutic effect of ketogenic diets is controversial, and the evidence varies between animal models (107). The various possible mechanisms of the antiepileptic effect of ketogenic diets have been reviewed (83, 107). Several of the signaling activities described above may be relevant, particularly modulation of potassium channels, FFAR3 activation, and promotion of GABA synthesis. Epigenetic modifications may also contribute to neuronal hyperexcitability and the long-term effects of epilepsy on the brain through persistent changes in gene expression (112). REST (RE1-silencing transcription factor) is a transcriptional repressor that recruits HDACs, among other chromatin-modifying enzymes, to help silence target genes. REST expression is increased in neurons after seizures and promotes aberrant neurogenesis. However, whether REST activity is helpful or harmful for seizure control differs in different seizure models (112). The contribution of epigenetic modifiers, including those that are modulated by BHB, to epilepsies and their long-term effects requires much further study.

Ironically, given the decades of study on the role of ketogenic diets in epilepsy, more molecular detail is known about the potential mechanisms of BHB in ameliorating dementia. Two major threads link BHB signaling with dementia: epigenetic modifications and neuronal hyperexcitability. There is a growing literature on the importance of epigenetic regulation in learning and memory, specifically in mouse models of dementia. Age-related impairments in learning and memory in wild-type mice are associated with alterations in histone acetylation (98), and treatment with HDAC inhibitors improves memory performance in both young and aged mice (42, 98). HDAC inhibitors also improve cognition in the CK-p25 dementia mouse model (28). HDAC2 appears to be the crucial mediator of these effects, as overexpression of HDAC2, but not HDAC1, impairs learning and memory in wild-type mice (42). Conversely, Hdac2 knockout mice show improved memory formation, which is not further improved by HDAC inhibitors (42). HDAC2 expression is increased in the brains of two mouse dementia models as well as the brains of humans with Alzheimer’s disease (39). One model of how HDAC inhibitors regulate cognition is via epigenetic priming, reminiscent of the poised transcriptional state of genes involved in muscle differentiation (40). The broader role of epigenetics in cognition and neurodegenerative disease has been reviewed (67, 68, 100).

The worlds of epilepsy and dementia have been linked through the finding that mouse models of Alzheimer’s disease show neuronal hyperexcitability and epileptiform spikes from dysfunctional inhibitory interneurons (97, 135). Epilepsy, an extreme manifestation of this hyperexcitability, is associated with more rapid cognitive decline in patients with Alzheimer’s disease (137). Promising treatments that reduce epileptiform spikes, including at least one commonly used antiepileptic drug, improve cognition in these models (114, 135). The various signaling activities by which BHB acts in epilepsy may thus be relevant to ameliorating cognitive decline in Alzheimer’s disease. In small studies, provision of BHB precursor molecules improves cognition in an Alzheimer’s mouse model (58) and in a patient with Alzheimer’s disease (93). Further exploration of the links between BHB signaling, epilepsy, and dementia may prove fruitful in generating new translational therapies.

Inhibition of the NLRP3 inflammasome could also prevent cognitive decline and dementia. β-amyloid protein, which aggregates into the amyloid plaques characteristic of Alzheimer’s disease, activates the NLRP3 inflammasome in microglia, the resident macrophage population in the brain, releasing inflammatory cytokines including IL-1β (reviewed in References 29 and 35). This activation is evident in the brain of humans with both mild cognitive impairment and Alzheimer’s disease, and Alzheimer’s mouse models that carry deficiencies in NLRP3 inflammasome components are protected from β-amyloid deposition and cognitive decline (50). Microglia, as critical mediators of brain inflammation, may be the site of integration of various BHB-related signals, including HCAR2 activation.

BHB Interactions With Aging Pathways

The hypothesis that BHB may play a broad role in regulating longevity and the effects of aging comes in part from the observation that many of the interventions that most consistently extend longevity across a wide range of organisms, such as dietary restriction and fasting, intrinsically involve ketogenesis and the production of BHB in mammals (92). The effects of such regimens on invertebrate, rodent, and human health have been reviewed and can include extended longevity, cognitive protections, reductions in cancer, and immune rejuvenation (75, 82). More specific interventions that promote ketogenesis, such as transgenic overexpression of FGF21, also extend life span in rodents (163). BHB itself extends longevity in C. elegans (24), and whether it would do so in rodents remains to be investigated.

Several of the signaling functions of BHB described above broadly regulate longevity and diseases of aging pathways, most prominently HDAC inhibition and inflammasome inhibition. The data from invertebrate organisms showing that reduction in class I HDAC activity extends life span, and generally acts through similar pathways as dietary restriction, have been reviewed (92). Briefly, deletion of Rpd3, the yeast and fly homolog of mammalian class I HDACs, extends replicative life span by 40−-50% in S. cerevisiae (61). Rpd3 deletion enhances ribosomal DNA silencing (61), the same mechanism by which overexpression of the sirtuin Sir2 enhances replicative longevity in S. cerevisiae (57). Drosophilids heterozygous for a null or hypomorphic Rpd3 allele show a 30−-40% extension of life span, with no further increase with caloric restriction (111). Both caloric restriction and reduced Rpd3 activity increase expression of Sir2 (111). Conversely, mutations in Sir2 block life span extension by either caloric restriction or Rpd3 mutations (110). In both organisms, then, modest reductions in HDAC activity (stronger reductions are lethal) extend life span via the same mechanisms as in dietary restriction and Sir2 expression.

Other possible longevity mechanisms downstream of Rpd3 in invertebrates include autophagy, which is regulated by histone acetylation of specific genes (152), and enhanced proteostasis through increased chaperone expression (164).

No life span data yet exist for reduced HDAC function in rodents. However, Hdac2 knockout mice display impaired IGF-1 signaling and are 25% smaller than normal (165), a potential longevity phenotype (87). Hdac2 knockout is also protective in models of tumorigenesis (165). Conditional knockouts in mouse embryonic fibroblasts and embryonic stem cells demonstrated roles for HDAC1 and HDAC2 in hematopoiesis (142) and stem cell differentiation (23). By analogy to the modest reductions in class I HDACs that enhance longevity in invertebrates, it may be of interest to determine whether heterozygous HDAC1/2 knockout mice, or mice treated with low-dose pharmacological HDAC inhibitors, have enhanced longevity.

An inducible compound heterozygote knockout of HDAC1 and HDAC2 does suppress one translatable age-related phenotype, cardiac hypertrophy, as do HDAC inhibitors (88). HDAC inhibitors ameliorate cardiac dysfunction in mouse diabetes models (14) and prevent maladaptive cardiac remodeling (162). The mechanism for the effect on cardiac hypertrophy appears to be inhibition of HDACs that suppress the activity of a mechanistic mTOR complex (88). This is one of several examples of intersections between BHB, its signaling effects, and mTOR/rapamycin, a canonical longevity-regulating pathway (55). As described above, mTOR is also a checkpoint in the activation of ketogenesis; inhibition of mTORC1 is required to activate the transcription factors and hormones that control ketogenesis (4, 117).

Inhibition of NLRP3 inflammasome activation might also have broad effects on aging and longevity, as reviewed in References 27 and 37. The NLRP3 inflammasome in particular has a wide range of activating stimuli, many of which accumulate with age such as urate, amyloid, cholesterol crystals, and excess glucose. The age-related phenotypes that may be ameliorated by its inhibition are similarly diverse: insulin resistance, bone loss, cognitive decline, and frailty. In two such examples, BHB inhibited NLRP3 inflammasome activation in urate crystal–activated macrophages, and ketogenic diet ameliorated flares of gout arthritis in rats (36). Whether genetic or pharmacological inhibition of the NLRP3 inflammasome would extend mammalian life span remains unknown, but the potential certainly exists for translational application to human diseases of aging.

Application And Future Directions

The ketone body BHB expresses a variety of molecular signaling functions, in addition to its role as a glucose-sparing energy carrier, that may influence a broad range of human diseases. There is sufficient evidence for several significant human diseases, including type 2 diabetes mellitus and Alzheimer’s dementia, in model organisms to justify human studies of BHB or a BHB-mimetic intervention. The diversity of age-associated diseases and pathways affected by BHB signaling suggests that therapies derived from BHB may hold promise for broadly enhancing health span and resilience in humans (91).

The translation of these effects into therapies that improve human health span requires the pursuit of two converging strategies: deeper mechanistic understanding of the downstream effects of BHB signals and improved systems for the targeted delivery of BHB for both experimental and therapeutic goals. Deeper mechanistic understanding would solidify some of the transitive connections described above. For example, BHB inhibits HDACs, and HDAC inhibition protects against cognitive decline in rodents; but does BHB protect against cognitive decline? Via HDAC inhibition? Which gene promoters are targeted? Establishing such links would permit rational design of human studies to test specific effects of BHB, with plausible biomarkers and intermediate outcomes. Improved delivery systems would facilitate both animal and human studies.

BHB-mimetic drugs, or ketomimetics, would recapitulate the desired activity of BHB. The key obstacles to exogenous delivery of BHB are its nature as an organic acid and the rapid catabolism of R-BHB. The quantity of exogenous BHB required to sustain blood levels over a long period would likely be harmful because of either excessive salt load or acidosis. Alternatively, approaches to ketomimetics include (a) the use of agents that activate endogenous ketogenesis in an otherwise normal dietary context, (b) the delivery of BHB prodrugs or precursors that avoid the acid/salt problem, and (c) the use of agents that phenocopy specific downstream signaling events. The last approach, such as using HCAR2 agonists or HDAC inhibitors, is tempting, but a perhaps crucial advantage of adapting BHB itself is utilizing the existing endogenous transporters and metabolite gradients to bring BHB to its sites of action. Esters of BHB are a promising approach to delivering BHB as a prodrug, but the expense of synthesis is challenging. Confirming whether such synthetic compounds need be enantiomerically pure, or indeed whether S-BHB has better pharmacokinetics for the desired signaling function, might help reduce cost.

The ketone body BHB, a fasting fuel and fasting signal, is emerging as a poster child of the endogenous metabolite that transmits signals from the environment to affect cellular function and human health. Researchers have made important strides in understanding the signaling functions of BHB, many of which have crucial implications for the management of human diseases. A deeper knowledge of the endogenous actions of BHB, and improved tools for delivering BHB or replicating its effects, offers promise for the improvement of human health span and longevity.

Source: John C. Newman, Eric Verdin. “β-Hydroxybutyrate-A Signaling Metabolite” Annual Review of Nutrition (2017): 37: 51–76.

An Ester of β-Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans *


In response to carbohydrate deprivation or prolonged fasting the ketone bodies, β-hydroxybutyrate (βHB) and acetoacetate (AcAc), are produced from the incomplete β-oxidation of fatty acids in the liver. Neither βHB nor AcAc are well utilized for synthesis of sterols or fatty acids in human or rat liver. To study the effects of ketones on cholesterol homeostasis a novel βHB ester (KE) ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) was synthesized and given orally to rats and humans as a partial dietary carbohydrate replacement. Rats maintained on a diet containing 30-energy % as KE with a concomitant reduction in carbohydrate had lower plasma cholesterol and mevalonate (-40 and -27 %, respectively) and in the liver had lower levels of the mevalonate precursors acetoacetyl-CoA and HMG-CoA (-33 and -54 %) compared to controls. Whole liver and membrane LDL-R as well as SREBP-2 protein levels were higher (+24, +67, and +91 %, respectively). When formulated into a beverage for human consumption subjects consuming a KE drink (30-energy %) had elevated plasma βHB which correlated with decreased mevalonate, a liver cholesterol synthesis biomarker. Partial replacement of dietary carbohydrate with KE induced ketosis and altered cholesterol homeostasis in rats. In healthy individuals an elevated plasma βHB correlated with lower plasma mevalonate.

Keywords: Cholesterol biosynthesis; Diabetes; Dietary supplement; Human; Ketogenic diet; Liver; Mass spectrometry; Statins; Triglycerides; β-Hydroxybutyrate.

Source: Martin F Kemper, Shireesh Srivastava, M Todd King, Kieran Clarke, Richard L Veech, Robert J Pawlosky. “An Ester of β-Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans” Lipids (2015): 50(12):1185-93.

Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation *


Optimising training and performance through nutrition strategies is central to supporting elite sportspeople, much of which has focused on manipulating the relative intake of carbohydrate and fat and their contributions as fuels for energy provision. The ketone bodies, namely acetoacetate, acetone and β-hydroxybutyrate (βHB), are produced in the liver during conditions of reduced carbohydrate availability and serve as an alternative fuel source for peripheral tissues including brain, heart and skeletal muscle. Ketone bodies are oxidised as a fuel source during exercise, are markedly elevated during the post-exercise recovery period, and the ability to utilise ketone bodies is higher in exercise-trained skeletal muscle. The metabolic actions of ketone bodies can alter fuel selection through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. Moreover, ketone bodies can act as signalling metabolites, with βHB acting as an inhibitor of histone deacetylases, an important regulator of the adaptive response to exercise in skeletal muscle. Recent development of ketone esters facilitates acute ingestion of βHB that results in nutritional ketosis without necessitating restrictive dietary practices. Initial reports suggest this strategy alters the metabolic response to exercise and improves exercise performance, while other lines of evidence suggest roles in recovery from exercise. The present review focuses on the physiology of ketone bodies during and after exercise and in response to training, with specific interest in exploring the physiological basis for exogenous ketone supplementation and potential benefits for performance and recovery in athletes.

Source: Mark Evans, Karl E Cogan, Brendan Egan. “Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation” Journal of Physiology (2017): 595(9):2857-2871.

Mixed salt compositions for producing elevated and sustained ketosis


Ketogenic compositions including a beta-hydroxybutyrate (BHB) mixed salt are formulated to induce or sustain ketosis in a subject to which the ketogenic compositions are administered. The BHB mixed salt is formulated to provide a biologically balanced set of cationic electrolytes and is formulated to avoid detrimental health effects associated with imbalanced electrolyte ratios. A ketogenic composition includes BHB salts of at least sodium, potassium, calcium, and magnesium. The BHB salts may also include at least other components such as a BHB compound containing other cations, such as transition metal cations (e.g., zinc or iron), a BHB-amino acid salts, medium chain fatty acid source, vitamin D3, flavorant, or other excipients.

Source: Millet, Gary. “Mixed salt compositions for producing elevated and sustained ketosis.” U.S. Patent Application No. 15/454,157.

Compositions and methods for producing elevated and sustained ketosis


Beta-hydroxybutyrate mineral salts in combination with medium chain fatty acids or an ester thereof such as medium chain triglycerides were used to induce ketosis, achieving blood ketone levels of (2-7 mmol/L), with or without dietary restriction. The combination results in substantial improvements in metabolic biomarkers related to insulin resistance, diabetes, weight loss, and physical performance in a short period of time. Further, the use of these supplements to achieve ketosis yields a significant elevation of blood ketones and reduction of blood glucose levels. Use of these substances does not adversely affect lipid profiles. By initiating rapid ketosis and accelerating the rate of keto-adaptation, this invention is useful for the avoidance of glucose withdrawal symptoms commonly experienced by individuals initiating a ketogenic diet and minimizes the loss of lean body mass during dietary restriction.

Source: D’Agostino, Dominic Paul, Patrick Arnold, and Shannon Kesl. “Compositions and methods for producing elevated and sustained ketosis.” (2015).

The use of nutritional supplements to induce ketosis and reduce symptoms associated with keto-induction: a narrative review *

Background: Adaptation to a ketogenic diet (keto-induction) can cause unpleasant symptoms, and this can reduce tolerability of the diet. Several methods have been suggested as useful for encouraging entry into nutritional ketosis (NK) and reducing symptoms of keto-induction. This paper reviews the scientific literature on the effects of these methods on time-to-NK and on symptoms during the keto-induction phase.

Methods: PubMed, Science Direct, CINAHL, MEDLINE, Alt Health Watch, Food Science Source and EBSCO Psychology and Behavioural Sciences Collection electronic databases were searched online. Various purported ketogenic supplements were searched along with the terms “ketogenic diet”, “ketogenic”, “ketosis” and ketonaemia (/ ketonemia). Additionally, author names and reference lists were used for further search of the selected papers for related references.

Results: Evidence, from one mouse study, suggests that leucine doesn’t significantly increase beta-hydroxybutyrate (BOHB) but the addition of leucine to a ketogenic diet in humans, while increasing the protein-to-fat ratio of the diet, doesn’t reduce ketosis. Animal studies indicate that the short chain fatty acids acetic acid and butyric acid, increase ketone body concentrations. However, only one study has been performed in humans. This demonstrated that butyric acid is more ketogenic than either leucine or an 8-chain monoglyceride. Medium-chain triglycerides (MCTs) increase BOHB in a linear, dose-dependent manner, and promote both ketonaemia and ketogenesis. Exogenous ketones promote ketonaemia but may inhibit ketogenesis.

Conclusions: There is a clear ketogenic effect of supplemental MCTs; however, it is unclear whether they independently improve time to NK and reduce symptoms of keto-induction. There is limited research on the potential for other supplements to improve time to NK and reduce symptoms of keto-induction. Few studies have specifically evaluated symptoms and adverse effects of a ketogenic diet during the induction phase. Those that have typically were not designed to evaluate these variables as primary outcomes, and thus, more research is required to elucidate the role that supplementation might play in encouraging ketogenesis, improve time to NK, and reduce symptoms associated with keto-induction.

Source: Cliff J. d C. Harvey, Grant M. Schofield, Micalla Williden. “The use of nutritional supplements to induce ketosis and reduce symptoms associated with keto-induction: a narrative review” Peer Journal (2018): 6: e4488.

MCT Powder

Weight-loss diet that includes consumption of medium-chain triacylglycerol oil leads to a greater rate of weight and fat mass loss than does olive oil *


Background: Clinical studies have shown that consumption of medium-chain triacylglycerols (MCTs) leads to greater energy expenditure than does consumption of long-chain triacylglycerols. Such studies suggest that MCT consumption may be useful for weight management.

Objective: We aimed to determine whether consumption of MCT oil improves body weight and fat loss compared with olive oil when consumed as part of a weight-loss program. Design: Forty-nine overweight men and women, aged 19-50 y, consumed either 18-24 g/d of MCT oil or olive oil as part of a weight-loss program for 16 wk. Subjects received weekly group weight-loss counseling. Body weight and waist circumference were measured weekly. Adipose tissue distribution was assessed at baseline and at the endpoint by use of dual-energy X-ray absorptiometry and computed tomography.

Results: Thirty-one subjects completed the study (body mass index: 29.8 +/- 0.4, in kg/m2). MCT oil consumption resulted in lower endpoint body weight than did olive oil (-1.67 +/- 0.67 kg, unadjusted P = 0.013). There was a trend toward greater loss of fat mass (P = 0.071) and trunk fat mass (P = 0.10) with MCT consumption than with olive oil. Endpoint trunk fat mass, total fat mass, and intraabdominal adipose tissue were all lower with MCT consumption than with olive oil consumption (all unadjusted P values < 0.05).

Conclusions: Consumption of MCT oil as part of a weight-loss plan improves weight loss compared with olive oil and can thus be successfully included in a weight-loss diet. Small changes in the quality of fat intake can therefore be useful to enhance weight loss.

Source: Marie-Pierre St-Onge, Aubrey Bosarge. “Weight-loss diet that includes consumption of medium-chain triacylglycerol oil leads to a greater rate of weight and fat mass loss than does olive oil” The American Journal of Clinical Nutrition (2008): 87(3):621-6.

Medium-chain triglycerides increase energy expenditure and decrease adiposity in overweight men *


Objective: The objectives of this study were to compare the effects of diets rich in medium-chain triglycerides (MCTs) or long-chain triglycerides (LCTs) on body composition, energy expenditure, substrate oxidation, subjective appetite, and ad libitum energy intake in overweight men.

Research methods and procedures: Twenty-four healthy, overweight men with body mass indexes between 25 and 31 kg/m2 consumed diets rich in MCT or LCT for 28 days each in a crossover randomized controlled trial. At baseline and after 4 weeks of each dietary intervention, energy expenditure was measured using indirect calorimetry, and body composition was analyzed using magnetic resonance imaging.

Results: Upper body adipose tissue (AT) decreased to a greater extent (p < 0.05) with functional oil (FctO) compared with olive oil (OL) consumption (-0.67 +/- 0.26 kg and -0.02 +/- 0.19 kg, respectively). There was a trend toward greater loss of whole-body subcutaneous AT volume (p = 0.087) with FctO compared with OL consumption. Average energy expenditure was 0.04 +/- 0.02 kcal/min greater (p < 0.05) on day 2 and 0.03 +/- 0.02 kcal/min (not significant) on day 28 with FctO compared with OL consumption. Similarly, average fat oxidation was greater (p = 0.052) with FctO compared with OL intake on day 2 but not day 28.

Discussion: Consumption of a diet rich in MCTs results in greater loss of AT compared with LCTs, perhaps due to increased energy expenditure and fat oxidation observed with MCT intake. Thus, MCTs may be considered as agents that aid in the prevention of obesity or potentially stimulate weight loss.

Source: Marie-Pierre St-Onge, Robert Ross, William D Parsons, Peter J H Jones. “Medium-chain triglycerides increase energy expenditure and decrease adiposity in overweight men” Obesity Research (2003): 11(3):395-402.

Greater rise in fat oxidation with medium-chain triglyceride consumption relative to long-chain triglyceride is associated with lower initial body weight and greater loss of subcutaneous adipose tissue *


Objective: Medium-chain triglyceride (MCT) consumption has been shown to increase energy expenditure (EE) and lead to greater losses of the adipose tissue in animals and humans. The objective of this research was to examine the relationship between body composition and thermogenic responsiveness to MCT treatment.

Design: Randomized, crossover, controlled feeding trial, with diets rich in either MCT or long-chain triglyceride (LCT) (as olive oil) for periods of 4 weeks each. Subjects: A total of 19 healthy overweight men aged (x+/-s.e.m.) 44.5+/-2.5 y with a body mass index of 27.8+/-0.5 kg/m2.

Measurements: EE and body composition were measured using indirect calorimetry and magnetic resonance imaging, respectively, at the baseline and end point of each feeding period. EE was measured for 30 min before consumption of a standard meal and for 5.5 h following the meal.

Results: Body weight (BW) decreased (P < 0.05) by 1.03+/-0.25 kg with MCT consumption compared to 0.62+/-0.29 kg with LCT consumption. The difference in average EE between MCT and LCT consumptions was related to initial BW, such that men with lower initial BW had a greater rise in EE with MCT consumption relative to LCT on day 28 (r=-0.472, P=0.04) but not day 2 (r=-0.368, P=0.12). Similar results were obtained with fat oxidation on day 28 (r=-0.553, P=0.01). The greater rise in fat oxidation with MCT compared to LCT consumption on day 2 tended to be related to greater loss of BW after MCT vs LCT consumption (r=-0.4075, P=0.08).

Conclusion: These data suggest that shunting of dietary fat towards oxidation results in diminished fat storage, as reflected by the loss of BW and subcutaneous adipose tissue. Furthermore, MCT consumption may stimulate EE and fat oxidation to a lower extent in men of greater BW compared to men of lower BW, indicative of the lower responsiveness to a rapidly oxidized fat by overweight men.

Source: M-P St-Onge, P J H Jones. “Greater rise in fat oxidation with medium-chain triglyceride consumption relative to long-chain triglyceride is associated with lower initial body weight and greater loss of subcutaneous adipose tissue” International Journal of Obesity and Related Metabolic Disorders (2003): 27(12):1565-71.

Impact of medium and long chain triglycerides consumption on appetite and food intake in overweight men *

Background: Medium chain triglycerides (MCT) enhance thermogenesis and may reduce food intake relative to long chain triglycerides (LCT). The goal of this study was to establish the effects of MCT on appetite and food intake and determine whether differences were due to differences in hormone concentrations.

Methods: Two randomized, crossover studies were conducted in which overweight men consumed 20 g of MCT or corn oil (LCT) at breakfast. Blood samples were obtained over 3 h. In Study 1 (n=10), an ad lib lunch was served after 3 h. In Study 2 (n=7), a pre-load containing 10 g of test oil was given at 3 h and lunch was served 1 h later. Linear mixed model analyses were performed to determine the effects of MCT and LCT oil on change in hormones and metabolites from fasting, adjusting for body weight. Correlations were computed between differences in hormones just before the test meals and differences in intakes after the two oils for Study 1 only.

Results: Food intake at the lunch test meal after the MCT pre-load (Study 2) was (mean ± SEM) 532 ± 389 kcal vs. 804 ± 486 kcal after LCT (P < 0.05). MCT consumption resulted in a lower rise in triglycerides (P = 0.014) and glucose (P = 0.066) and a higher rise in peptide YY (P = 0.017) and leptin (P = 0.036) compared to LCT (combined data). Correlations between differences in hormone levels (GLP-1, PYY) and differences in food intake were in the opposite direction to expectations.

Conclusion: MCT consumption reduced food intake acutely but this does not seem to be mediated by changes in GLP-1, PYY, and insulin.

Source: Marie-Pierre St-Onge, Brian Mayrsohn, Majella O’Keeffe, Harry R. Kissileff, Arindam Roy Choudhury, Blandine Laferrère. “Impact of medium and long chain triglycerides consumption on appetite and food intake in overweight men” European Journal of Clinical Nutrition (2014): 68(10): 1134–1140.

Weight-loss diet that includes consumption of medium-chain triacylglycerol oil leads to a greater rate of weight and fat mass loss than does olive oil *


Background: Clinical studies have shown that consumption of medium-chain triacylglycerols (MCTs) leads to greater energy expenditure than does consumption of long-chain triacylglycerols. Such studies suggest that MCT consumption may be useful for weight management.

Objective: We aimed to determine whether consumption of MCT oil improves body weight and fat loss compared with olive oil when consumed as part of a weight-loss program. Design: Forty-nine overweight men and women, aged 19-50 y, consumed either 18-24 g/d of MCT oil or olive oil as part of a weight-loss program for 16 wk. Subjects received weekly group weight-loss counseling. Body weight and waist circumference were measured weekly. Adipose tissue distribution was assessed at baseline and at the endpoint by use of dual-energy X-ray absorptiometry and computed tomography.

Results: Thirty-one subjects completed the study (body mass index: 29.8 +/- 0.4, in kg/m2). MCT oil consumption resulted in lower endpoint body weight than did olive oil (-1.67 +/- 0.67 kg, unadjusted P = 0.013). There was a trend toward greater loss of fat mass (P = 0.071) and trunk fat mass (P = 0.10) with MCT consumption than with olive oil. Endpoint trunk fat mass, total fat mass, and intraabdominal adipose tissue were all lower with MCT consumption than with olive oil consumption (all unadjusted P values < 0.05).

Conclusions: Consumption of MCT oil as part of a weight-loss plan improves weight loss compared with olive oil and can thus be successfully included in a weight-loss diet. Small changes in the quality of fat intake can therefore be useful to enhance weight loss.

Source: Marie-Pierre St-Onge, Aubrey Bosarge. “Weight-loss diet that includes consumption of medium-chain triacylglycerol oil leads to a greater rate of weight and fat mass loss than does olive oil” Clinical Nutrition (2008): 87(3):621-6.


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