Impact of Acutely Increased Endogenous- and Exogenous Ketone Bodies on FGF21 Levels in Humans.

PURPOSE: Fibroblast growth factor (FGF) 21 is a circulating hormone with metabolic regulatory importance. In mice, FGF21 increases in response to a ketogenic diet and fasting. In humans, a similar increase is only observed after prolonged starvation. We aim to study the acute effects of ketone bodies on circulating FGF21 levels in humans. METHODS: Participants from three randomized, placebo-controlled crossover studies, with increased endogenous or exogenous ketone bodies, were included. Study 1: patients with type 1 diabetes (T1D) (n = 9) were investigated after a) insulin deprivation and lipopolysaccharide (LPS) injection and b) insulin-controlled euglycemia. Study 2: patients with T1D (n = 9) were investigated after a) total insulin deprivation for 9 hours and b) insulin-controlled euglycemia. Study 3: Healthy adults (n = 9) were examined during a) 3-hydroxybutyrate (OHB) infusion and b) saline infusion. Plasma FGF21 was measured with immunoassay in serial samples. RESULTS: Circulating OHB levels were significantly increased to 1.3, 1.5, and 5.5 mmol/l in the three studies, but no correlations with FGF21 levels were found. Also, no correlations between FGF21, insulin, or glucagon were found. Insulin deprivation and LPS injection resulted in increased plasma FGF21 levels at t = 120 min (p = .005) which normalized at t = 240 min. CONCLUSION: We found no correlation between circulating FGF21 levels and levels of ketone bodies. This suggests that it is not ketosis per se which controls FGF21 production, but instead a rather more complex regulatory mechanism. TRIAL REGISTRATION: clinicaltrials.gov ID number: Study 1: NCT02157155 (5/6-2014), study 2: NCT02077348 (4/3-2014), and study 3: NCT02357550 (6/2-2015).

Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade.

Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.

Migraine and Diet.

Migraine is characterized by recurrent attacks of disabling headaches, often accompanied by sensory and motor disturbances. Clinical manifestations of migraine are influenced by dietary behaviors and dietary elements. Several dietary triggers for migraine have been identified, leading to the definition of strategies such as elimination diets, ketogenic diets, and comprehensive diets, mainly to help prevent migraine. Although inconsistency is present in the literature and no consensus exists, the available data are promising in supporting beneficial dietary interventions for some migraine patients. Several factors influence the net outcome, including age, sex, genetics, and environmental factors. Advancement in understanding the underlying mechanisms of migraine pathogenesis and how dietary factors can interfere with those mechanisms has encouraged investigators to consider diet as a disease-modifying agent, which may also interfere with the gut-brain axis or the epigenetics of migraine. Future work holds potential for phenotyping migraine patients and offering personalized recommendations in line with biopsychosocial models for the management of migraine. Diet, as an important element of lifestyle, is a modifiable aspect that needs further attention. Well-designed, systematic, and mechanism-driven dietary research is needed to provide evidence-based dietary recommendations specific to migraine. This narrative review aims to present the current status and future perspective on diet and migraine, in order to stimulate further research and awareness.

Induced Ketosis as a Treatment for Neuroprogressive Disorders: Food for Thought?

Induced ketosis (or ketone body ingestion) can ameliorate several changes associated with neuroprogressive disorders, including schizophrenia, bipolar disorder, and major depressive disorder. Thus, the effects of glucose hypometabolism can be bypassed through the entry of beta-hydroxybutyrate, providing an alternative source of energy to glucose. The weight of evidence suggests that induced ketosis reduces levels of oxidative stress, mitochondrial dysfunction, and inflammation-core features of the above disorders. There are also data to suggest that induced ketosis may be able to target other molecules and signaling pathways whose levels and/or activity are also known to be abnormal in at least some patients suffering from these illnesses such as peroxisome proliferator-activated receptors, increased activity of the Kelch-like ECH-associated protein/nuclear factor erythroid 2-related factor 2, Sirtuin-1 nuclear factor-κB p65, and nicotinamide adenine dinucleotide (NAD). This review explains the mechanisms by which induced ketosis might reduce mitochondrial dysfunction, inflammation, and oxidative stress in neuropsychiatric disorders and ameliorate abnormal levels of molecules and signaling pathways that also appear to contribute to the pathophysiology of these illnesses. This review also examines safety data relating to induced ketosis over the long term and discusses the design of future studies.

Utility of Ketone Supplementation to Enhance Physical Performance: A Systematic Review.

Ingesting exogenous ketone bodies has been touted as producing ergogenic effects by altering substrate metabolism; however, research findings from recent studies appear inconsistent. This systematic review aimed to aggregate data from the current literature to examine the impact of consuming ketone supplements on enhancing physical performance. A systematic search was performed for randomized controlled trials that measured physical performance outcomes in response to ingesting exogenous ketone supplements compared with a control (nutritive or non-nutritive) in humans. A total of 161 articles were screened. Data were extracted from 10 eligible studies (112 participants; 109 men, 3 women ) containing 16 performance outcomes [lower-body power (n = 8) and endurance performance (n = 8)]. Ketone supplements were grouped as ketone esters (n = 8) or ketone salts/precursors (n = 8). Of the 16 performance outcomes identified by the systematic review, 3 reported positive, 10 reported null, and 3 reported negative effects of ketone supplementation on physical performance compared with controls. Heterogeneity was detected for lower-body power ( Q = 40, I2 = 83%, P < 0.01) and endurance performance (Q = 95, I2 = 93%, P < 0.01) between studies. Similarly high levels of heterogeneity were detected in studies providing ketone esters (Q = 111, I2 = 93%, P < 0.01), and to a lesser extent studies with ketone salts/precursors (Q = 25, I2 = 72%, P < 0.01). Heterogeneity across studies makes it difficult to conclude any benefit or detriment to consuming ketone supplements on physical performance. This systematic review discusses factors within individual studies that may contribute to discordant outcomes across investigations to elucidate if there is sufficient evidence to warrant recommendation of consuming exogenous ketone supplements to enhance physical performance.

Ketogenic and anaplerotic dietary modifications ameliorate seizure activity in Drosophila models of mitochondrial encephalomyopathy and glycolytic enzymopathy.

Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, with a wide array of downstream effects at the genetic, protein, and metabolite level that may mediate seizure protection. We have recently shown that a Drosophila model of human ME (ATP61) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. We have found that reduction of glycolysis does not confer seizure protection, but that dietary supplementation with ketone bodies or the anaplerotic lipid triheptanoin, which directly replenishes the citric acid cycle, can mimic the success of the ketogenic diet even in the presence of standard carbohydrate levels. We have also shown that the proper functioning of the citric acid cycle is crucial to the success of the KD in the context of ME. Furthermore, our data reveal that multiple seizure models, in addition to ATP61, are treatable with the ketogenic diet. Importantly, one of these mutants is TPIsugarkill, which models human glycolytic enzymopathy, an incurable metabolic disorder with severe neurological consequences. Overall, these studies reveal widespread success of the KD in Drosophila, further cementing its status as an excellent model for studies of KD treatment and mechanism, and reveal key insights into the therapeutic potential of dietary therapy against neuronal hyperexcitability in epilepsy and metabolic disease.

Long-term ketone body therapy of severe multiple acyl-CoA dehydrogenase deficiency: A case report.

OBJECTIVES: Multiple acyl-CoA dehydrogenase deficiency (MADD) is the most severe disorder of mitochondrial fatty acid ß-oxidation. Treatment of this disorder is difficult because the functional loss of the electron transfer flavoprotein makes energy supply from fatty acids impossible. Acetyl-CoA, provided by exogenous ketone bodies such as NaßHB, is the only treatment option in severe cases. Short-term therapy attempts have shown positive results. To our knowledge, no reports exist concerning long-term application of ketone body salts in patients with severe MADD. METHODS: This case report is a detailed retrospective metabolic analysis of a boy with severe MADD. Treatment with sodium ß-hydroxybutyrate (NaßHB) started 8 d after birth using gradually increasing doses. In the initial phase, metabolic and acid-base parameters were checked multiple times a day. After 8 y of standardized therapy with 16 g NaßHB, substitution with calcium ß-hydroxybutyrate (CaßHB) was attempted. In addition to the ß-hydroxybutyrate (ßHB) supplementation, continuous adjustments were made to the child's nutrition to provide necessary nutrients. RESULTS: Treatment with ßHB salts leads to adverse effects like gastrointestinal discomfort and alkalosis. Measured concentrations of ßHB were predominantly at 0.1 mmol/L or below detectable concentration. Nutritional therapy based on amino acid and acylcarnitine profiles is a necessary part of the therapy in MADD. CONCLUSIONS: Therapy with NaßHB is lifesaving in cases of severe MADD but can have significant adverse effects. Supplementation with CaßHB led to gastrointestinal discomfort and had no additional positive clinical effect. The determined tolerable dose of ßHB salt for long-term therapy was not high enough for a notable increase of ßHB concentrations in blood.

Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans: Reduced glucose uptake, unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized, controlled trial.

Ketone bodies are neuroprotective in neurological disorders such as epilepsy. We randomly studied nine healthy human subjects twice-with and without continuous infusion of 3-hydroxybutyrate-to define potential underlying mechanisms, assessed regionally (parietal, occipital, temporal, cortical grey, and frontal) by PET scan. During 3-hydroxybutyrate infusions concentrations increased to 5.5±0.4 mmol/l and cerebral glucose utilisation decreased 14%, oxygen consumption remained unchanged, and cerebral blood flow increased 30%. We conclude that acute 3-hydroxybutyrate infusion reduces cerebral glucose uptake and increases cerebral blood flow in all measured brain regions, without detectable effects on cerebral oxygen uptake though oxygen extraction decreased. Increased oxygen supply concomitant with unchanged oxygen utilisation may contribute to the neuroprotective effects of ketone bodies.

The ketogenic diet affects the social behavior of young male rats.

The positive effects of the ketogenic diet (KD) on social behavior have been recently reported in patients and rodent models of autism spectrum disorder (ASD). Given the beneficial effects of the KD on epilepsy, mitochondrial function, carbohydrate metabolism, and inflammation, treatment based on the KD has the potential to reduce some of the ASD-associated symptoms, including abnormal social interactions. It is not known whether the KD influences sociability by reducing the pathological processes underlying ASD or through some independent mechanism. The aim of the present study was to evaluate the influence of the KD on the social behavior of rats. Four-week-old Long-Evans males were treated with the KD for 4 subsequent weeks. Afterwards, behavioral tests were performed in order to evaluate sociability, locomotor activity, working memory, and anxiety-related behaviors. Additionally we performed the social interaction test in animals that were receiving ß-hydroxybutyrate or acetone. We have observed that rats fed with the KD showed increased social exploration in three different experimental settings. We did not observe any changes in the level of social interactions in animals treated with exogenous ketone bodies. The results did not show any difference in mobility or anxiety-related behaviors or working memory between the animals fed with the KD or standard rodent chow. In conclusion, we showed that the KD affects the social behavior of wild-type young adult male rats, which was not associated with other behavioral changes.

Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD mouse model of Alzheimer's disease.

In patients with Alzheimer's disease (AD) and in a triple transgenic (3xTgAD) mouse model of AD low glucose metabolism in the brain precedes loss of memory and cognitive decline. The metabolism of ketones in the brain by-passes glycolysis and therefore may correct several deficiencies that are associated with glucose hypometabolism. A dietary supplement composed of an ester of D-ß-hydroxybutyrate and R-1,3 butane diol referred to as ketone ester (KE) was incorporated into a rodent diet and fed to 3xTgAD mice for 8 months. At 16.5 months of age animals were killed and brains dissected. Analyses were carried out on the hippocampus and frontal cortex for glycolytic and TCA (Tricarboxylic Acid) cycle intermediates, amino acids, oxidized lipids and proteins, and enzymes. There were higher concentrations of d-ß-hydroxybutyrate in the hippocampus of KE-fed mice where there were also higher concentrations of TCA cycle and glycolytic intermediates and the energy-linked biomarker, N-acetyl aspartate compared to controls. In the hippocampi of control-fed animals the free mitochondrial [NAD+ ]/[NADH] ratio were highly oxidized, whereas, in KE-fed animals the mitochondria were reduced. Also, the levels of oxidized protein and lipids were lower and the energy of ATP hydrolysis was greater compared to controls. 3xTgAD mice maintained on a KE-supplemented diet had higher concentrations of glycolytic and TCA cycle metabolites, a more reduced mitochondrial redox potential, and lower amounts of oxidized lipids and proteins in their hippocampi compared to controls. The KE offers a potential therapy to counter fundamental metabolic deficits common to patients and transgenic models. Read the Editorial Highlight for this article on page 162.

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 ß-hydroxybutyrate (ßHB), 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 ßHB 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 ßHB 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.

Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype?

Elite athletes and coaches are in a constant search for training methods and nutritional strategies to support training and recovery efforts that may ultimately maximize athletes' performance. Recently, there has been a re-emerging interest in the role of ketone bodies in exercise metabolism, with considerable media speculation about ketone body supplements being routinely used by professional cyclists. Ketone bodies can serve as an important energy substrate under certain conditions, such as starvation, and can modulate carbohydrate and lipid metabolism. Dietary strategies to increase endogenous ketone body availability (i.e., a ketogenic diet) require a diet high in lipids and low in carbohydrates for ~4 days to induce nutritional ketosis. However, a high fat, low carbohydrate ketogenic diet may impair exercise performance via reducing the capacity to utilize carbohydrate, which forms a key fuel source for skeletal muscle during intense endurance-type exercise. Recently, ketone body supplements (ketone salts and esters) have emerged and may be used to rapidly increase ketone body availability, without the need to first adapt to a ketogenic diet. However, the extent to which ketone bodies regulate skeletal muscle bioenergetics and substrate metabolism during prolonged endurance-type exercise of varying intensity and duration remains unknown. Therefore, at present there are no data available to suggest that ingestion of ketone bodies during exercise improves athletes' performance under conditions where evidence-based nutritional strategies are applied appropriately.

A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease.

BACKGROUND: Providing ketone bodies to the brain can bypass metabolic blocks to glucose utilization and improve function in energy-starved neurons. For this, plasma ketones must be elevated well above the ≤ 0.2 mM default concentrations normally prevalent. Limitations of dietary methods currently used to produce therapeutic hyperketonemia have stimulated the search for better approaches. METHOD: Described herein is a new way to produce therapeutic hyperketonemia, entailing prolonged oral administration of a potent ketogenic agent--ketone monoester (KME)--to a patient with Alzheimer's disease dementia and a pretreatment Mini-Mental State Examination score of 12. RESULTS: The patient improved markedly in mood, affect, self-care, and cognitive and daily activity performance. The KME was well tolerated throughout the 20-month treatment period. Cognitive performance tracked plasma ß-hydroxybutyrate concentrations, with noticeable improvements in conversation and interaction at the higher levels, compared with predose levels. CONCLUSION: KME-induced hyperketonemia is robust, convenient, and safe, and the ester can be taken as an oral supplement without changing the habitual diet.

The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury.

The postinjury period of glucose metabolic depression is accompanied by adenosine triphosphate decreases, increased flux of glucose through the pentose phosphate pathway, free radical production, activation of poly-ADP ribose polymerase via DNA damage, and inhibition of glyceraldehyde dehydrogenase (a key glycolytic enzyme) via depletion of the cytosolic NAD pool. Under these post-brain injury conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. Ketone bodies are the only known natural alternative substrate to glucose for cerebral energy metabolism. While it has been demonstrated that other fuels (pyruvate, lactate, and acetyl-L-carnitine) can be metabolized by the brain, ketones are the only endogenous fuel that can contribute significantly to cerebral metabolism. Preclinical studies employing both pre- and postinjury implementation of the ketogenic diet have demonstrated improved structural and functional outcome in traumatic brain injury (TBI) models, mild TBI/concussion models, and spinal cord injury. Further clinical studies are required to determine the optimal method to induce cerebral ketone metabolism in the postinjury brain, and to validate the neuroprotective benefits of ketogenic therapy in humans.

Ketone esters increase brown fat in mice and overcome insulin resistance in other tissues in the rat.

Brown adipose tissue (BAT) is classically activated by sympathetic nervous stimulation resulting from exposure to cold. Feeding a high-fat diet also induces development of brown fat, but is decreased by caloric restriction. Blood ketone bodies, which function as alternative energy substrates to glucose, are increased during caloric restriction. Here we discuss the unexpected observation that feeding an ester of ketone bodies to the mouse, which increases blood ketone body concentrations, results in an activation of brown fat. The mechanism of this activation of brown fat is similar to that occurring from cold exposure in that cyclic adenosine monophosphate (AMP) levels are increased as are levels of the transcription factor cyclic AMP-responsive element-binding protein, which is also increased by ketone ester feeding. Other effects of feeding ketone esters, in addition to their ability to induce brown fat, are discussed such as their ability to overcome certain aspects of insulin resistance and to ameliorate the accumulation of amyloid and phosphorylated tau protein in brain, and improve cognitive function, in a triple transgenic mouse model of Alzheimer's disease.

Stroke outcome in the ketogenic state--a systematic review of the animal data.

As a predictor of potential clinical outcome, we performed a systematic review of controlled studies that assessed experimental stroke outcome in rodents maintained on special diets (calorie restriction and ketogenic diet) or following the direct administration of ketone bodies. Pre-clinical studies were identified by searching web databases and the reference lists of relevant original articles and reviews. Sixteen published studies (a total of 733 experimental animals) met specific criteria and were analyzed using Cochrane Review Manager software. This resulted in objective evidence to suggest beneficial effects of the ketogenic pathway on pathological and functional outcomes following experimental stroke.

Central infusion of ketone bodies modulates body weight and hepatic insulin sensitivity by modifying hypothalamic leptin and insulin signaling pathways in type 2 diabetic rats.

Although the effects of ketogenic diets on energy and glucose homeostasis have been controversial, elevation of serum ketone levels by subcutaneous injection of ß-hydroxybutyrate (BHB) can improve glucose homeostasis. Ketones may work through the brain; therefore, we evaluated whether the intracerebroventricular (ICV) infusion of ß-hydroxybutyrates would also modulate peripheral energy and glucose homeostasis, and through what mechanisms, in diabetic rats fed a high fat diet in short- and long-term studies. Short-term (3h) central injection of BHB (50 µg/h) improved serum glucose levels and peripheral insulin sensitivity compared to the artificial cerebrospinal fluid (CSF) group among 90% pancreatectomized (Px) diabetic rats, but not in non-diabetic Sham rats. In addition to short-term infusion, long-term (28 days) central infusion of BHB (12 µg/h) elevated serum BHB levels. Long-term infusion of BHB potentiated leptin and insulin signaling in the hypothalamus to slightly decrease body weight in Px rats. Central BHB infusion had a greater effect on peripheral glucose metabolism than overall energy metabolism. Hepatic insulin signaling (tyrosine phosphorylation of IRS2→serine phosphorylation of Akt→reduced expression of PEPCK) was potentiated and hepatic glucose production in the hyperinsulinemic state was suppressed in the diabetic rats. In addition, glucose tolerance was improved by central BHB infusion through enhanced whole body glucose disposal rates, but insulin secretion was not affected in the diabetic rats. In conclusion, mild ketosis by central infusion of ketones improves energy and glucose metabolism through the potentiation of leptin and insulin signaling in the hypothalamus of diabetic rats.

Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, ß-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gßγ-PLCß-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.

Central injection of ketone body suppresses luteinizing hormone release via the catecholaminergic pathway in female rats.

Ketosis is found in various pathophysiological conditions, including diabetes and starvation, that are accompanied by suppression of gonadal activity. The aim of the present study was to determine the role of ketone body in the brain in regulating pulsatile luteinizing hormone (LH) secretion in female rats. Injection of 3-hydroxybutyrate (3HB), a ketone body, into the fourth cerebroventricle (4V) induced suppression of pulsatile LH secretion in a dose-dependent manner in ovariectomized (OVX) rats with an estradiol (E2) implant producing diestrus plasma E2 levels. Plasma glucose and corticosterone levels increased immediately after the 4V 3HB injection, suggesting that the treatment caused a hunger response. The 3HB-induced suppression of LH pulses might be mediated by noradrenergic inputs to the hypothalamic paraventricular nucleus (PVN) because a local injection of α-methyl- p-tyrosine, a catecholamine synthesis inhibitor, into the PVN blocked 3HB-induced suppression of LH pulses and PVN noradrenaline release was increased by 4V 3HB injection in E2-primed OVX rats. These results suggest that ketone body sensed by a central energy sensor in the hindbrain may suppress gonadotropin release via noradrenergic inputs to the PVN under ketosis.

Ketone bodies as a therapeutic for Alzheimer's disease.

An early feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, beta-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.