The Experts below are selected from a list of 20211 Experts worldwide ranked by ideXlab platform
Richard L Veech - One of the best experts on this subject based on the ideXlab platform.
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Ketone Bodies mimic the life span extending properties of caloric restriction
Iubmb Life, 2017Co-Authors: Richard L Veech, Patrick C Bradshaw, Kieran Clarke, William Curtis, Robert J Pawlosky, Todd M KingAbstract:The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3 ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of Ketone Bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary Ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The Ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of Ketone Bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of Ketone Bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of Ketone Bodies. An exogenous Ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. © 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5):305-314, 2017.
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metabolite regulation of nucleo cytosolic trafficking of carbohydrate response element binding protein chrebp role of Ketone Bodies
Journal of Biological Chemistry, 2013Co-Authors: Tsutomu Nakagawa, Richard L Veech, Robert Pawlosky, Max R Wynn, Kosaku UyedaAbstract:The carbohydrate response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in converting excess carbohydrate to storage fat in liver. In response to changing glucose levels, ChREBP activity is regulated by nucleo-cytoplasmic shuttling of ChREBP via interactions with 14-3-3 proteins and importins. The nuclear/cytosol trafficking is regulated partly by phosphorylation/dephosphorylation of serine 196 mediated by cAMP-dependent protein kinase and protein phosphatase. We show here that protein-free extracts of starved and high fat-fed livers contain metabolites that activate interaction of ChREBP·14-3-3 and inhibit the ChREBP/importin α interaction, resulting in cytosolic localization. These metabolites were identified as β-hydroxybutyrate and acetoacetate. Nuclear localization of GFP-ChREBP is rapidly inhibited in hepatocytes incubated in β-hydroxybutyrate or fatty acids, and the observed inhibition is closely correlated with the production of Ketone Bodies. These observations show that Ketone Bodies play an important role in the regulation of ChREBP activity by restricting ChREBP localization to the cytoplasm, thus inhibiting fat synthesis during periods of ketosis.
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the therapeutic implications of Ketone Bodies the effects of Ketone Bodies in pathological conditions ketosis ketogenic diet redox states insulin resistance and mitochondrial metabolism
Prostaglandins Leukotrienes and Essential Fatty Acids, 2004Co-Authors: Richard L VeechAbstract:The effects of Ketone body metabolism suggests that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. These inferences follow directly from the metabolic effects of ketosis and the higher inherent energy present in d-beta-hydroxybutyrate relative to pyruvate, the normal mitochondrial fuel produced by glycolysis leading to an increase in the DeltaG' of ATP hydrolysis. The large categories of disease for which Ketones may have therapeutic effects are:(1)diseases of substrate insufficiency or insulin resistance,(2)diseases resulting from free radical damage,(3)disease resulting from hypoxia. Current ketogenic diets are all characterized by elevations of free fatty acids, which may lead to metabolic inefficiency by activation of the PPAR system and its associated uncoupling mitochondrial uncoupling proteins. New diets comprised of Ketone Bodies themselves or their esters may obviate this present difficulty.
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the therapeutic implications of Ketone Bodies the effects of Ketone Bodies in pathological conditions ketosis ketogenic diet redox states insulin resistance and mitochondrial metabolism
Prostaglandins Leukotrienes and Essential Fatty Acids, 2004Co-Authors: Richard L VeechAbstract:Abstract The effects of Ketone body metabolism suggests that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. These inferences follow directly from the metabolic effects of ketosis and the higher inherent energy present in d-β-hydroxybutyrate relative to pyruvate, the normal mitochondrial fuel produced by glycolysis leading to an increase in the Δ G ′ of ATP hydrolysis. The large categories of disease for which Ketones may have therapeutic effects are: (1)diseases of substrate insufficiency or insulin resistance, (2)diseases resulting from free radical damage, (3)disease resulting from hypoxia. Current ketogenic diets are all characterized by elevations of free fatty acids, which may lead to metabolic inefficiency by activation of the PPAR system and its associated uncoupling mitochondrial uncoupling proteins. New diets comprised of Ketone Bodies themselves or their esters may obviate this present difficulty.
Brendan Egan - One of the best experts on this subject based on the ideXlab platform.
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anticatabolic effects of Ketone Bodies in skeletal muscle
Trends in Endocrinology and Metabolism, 2019Co-Authors: Andrew P Koutnik, Dominic P Dagostino, Brendan EganAbstract:The Ketone Bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) are the subject of renewed interest given recently established pleiotropic effects regulating inflammation, oxidative stress, and gene expression. Anticatabolic effects of β-hydroxybutyrate have recently been demonstrated in human skeletal muscle under inflammatory insult, thereby expanding upon the wide-ranging therapeutic applications of nutritional ketosis.
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metabolism of Ketone Bodies during exercise and training physiological basis for exogenous supplementation
The Journal of Physiology, 2017Co-Authors: Mark Evans, Karl E Cogan, Brendan EganAbstract: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.
Luc Pellerin - One of the best experts on this subject based on the ideXlab platform.
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Hypothalamic sensing of Ketone Bodies after prolonged cerebral exposure leads to metabolic control dysregulation
Scientific Reports, 2016Co-Authors: Lionel Carneiro, Sarah Geller, Audrey Hébert, Cendrine Repond, Xavier Fioramonti, Corinne Leloup, Luc PellerinAbstract:Ketone Bodies have been shown to transiently stimulate food intake and modify energy homeostasis regulatory systems following cerebral infusion for a moderate period of time (< 6 hours). As Ketone Bodies are usually enhanced during episodes of fasting, this effect might correspond to a physiological regulation. In contrast, Ketone Bodies levels remain elevated for prolonged periods during obesity, and thus could play an important role in the development of this pathology. In order to understand this transition, Ketone Bodies were infused through a catheter inserted in the carotid to directly stimulate the brain for a period of 24 hours. Food ingested and blood circulating parameters involved in metabolic control as well as glucose homeostasis were determined. Results show that Ketone Bodies infusion for 24 hours increased food intake associated with a stimulation of hypothalamic orexigenic neuropeptides. Moreover, insulinemia was increased and caused a decrease in glucose production despite an increased resistance to insulin. The present study confirms that Ketone Bodies reaching the brain stimulates food intake. Moreover, we provide evidence that a prolonged hyperKetonemia leads to a dysregulation of energy homeostasis control mechanisms. Finally, this study shows that brain exposure to Ketone Bodies alters insulin signaling and consequently glucose homeostasis.
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Evidence for hypothalamic Ketone Bodies sensing: impact on food intake and peripheral metabolic responses in mice
AJP - Endocrinology and Metabolism, 2016Co-Authors: Lionel Carneiro, Sarah Geller, Audrey Hébert, Cendrine Repond, Xavier Fioramonti, Corinne Amiot Leloup, Luc PellerinAbstract:Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of Ketone Bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral Ketone Bodies on food intake and energy homeostasis regulation. A carotid infusion of Ketone Bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in Ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain Ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to Ketone Bodies sensed by the brain, as blood Ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of Ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain Ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.
Qun Wang - One of the best experts on this subject based on the ideXlab platform.
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Ketone Bodies in Neurological Diseases: Focus on Neuroprotection and Underlying Mechanisms.
Frontiers in neurology, 2019Co-Authors: Huajun Yang, Wei Shan, Fei Zhu, Qun WangAbstract:There is growing evidence that Ketone Bodies, which are derived from fatty acid oxidation and usually produced in fasting state or on high-fat diets have broad neuroprotective effects. Although the mechanisms underlying the neuroprotective effects of Ketone Bodies have not yet been fully elucidated, studies in recent years provided abundant shreds of evidence that Ketone Bodies exert neuroprotective effects through possible mechanisms of anti-oxidative stress, maintaining energy supply, modulating the activity of deacetylation and inflammatory responses. Based on the neuroprotective effects, the ketogenic diet has been used in the treatment of several neurological diseases such as refractory epilepsy, Parkinson's disease, Alzheimer's disease, and traumatic brain injury. The ketogenic diet has great potential clinically, which should be further explored in future studies. It is necessary to specify the roles of components in Ketone Bodies and their therapeutic targets and related pathways to optimize the strategy and efficacy of ketogenic diet therapy in the future.
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Ketone Bodies Inhibit the Opening of Acid-Sensing Ion Channels (ASICs) in Rat Hippocampal Excitatory Neurons in vitro.
Frontiers in Neurology, 2019Co-Authors: Wei Shan, Qinlan Xu, Jianping Wu, Qun WangAbstract:Objectives: Despite the long-term efficacy of antiepileptic drug treatments, frequent attacks of drug-resistant epilepsy necessitate the development of new antiepileptic drug therapy targets. The ketogenic diet is a high-fat, low-carbohydrate diet that has been shown to be effective in treating drug-resistant epilepsy, although the mechanism is yet unclear. In the ketogenic diet, excess fat is metabolized into Ketone Bodies (including acetoacetic acid, β-hydroxybutyric acid, and acetone). The present study explored the effect of Ketone Bodies on acid-sensing ion channels and provided a theoretical basis for the study of new targets of antiepileptic drugs based on” Ketone body-acid sensing ion channels.” Methods: In this study, rat primary cultured hippocampal neurons were used. The effects of acetoacetic acid, β-hydroxybutyric acid, and acetone on the open state of acid-sensing ion channels of hippocampal neurons were investigated by the patch-clamp technique. Results: At pH 6.0, the addition of acetoacetic acid, β-hydroxybutyric acid, and acetone in the extracellular solution markedly weakened the currents of acid-sensing ion channels. The three Ketone Bodies significantly inhibited the opening of the acid-sensing ion channels on the surface of the hippocampal neurons, and 92%, 47%, and 77%, respectively. Conclusions: Ketone Bodies significantly inhibit the opening of acid-sensing ion channels. However, a new target for antiepileptic drugs on acid-sensing ion channels is yet to be investigated.
Raymond F Novak - One of the best experts on this subject based on the ideXlab platform.
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effects of fatty acids and Ketone Bodies on cytochromes p450 2b 4a and 2e1 expression in primary cultured rat hepatocytes
Archives of Biochemistry and Biophysics, 1997Co-Authors: Richard C Zangar, Raymond F NovakAbstract:Abstract CYP2B, CYP4A, and CYP2E1 mRNA levels are elevated in response to pathophysiological conditions, such as diabetes, high-fat diet, and fasting, in which lipids and Ketone Bodies are increased. In order to avoid confounding hormonal effects, we utilized primary rat hepatocytes to examine whether Ketone Bodies or fatty acids altered CYP2B, CYP4A, or CYP2E1 expression. Ketone Bodies increased CYP2B mRNA and protein levels, but failed to alter CYP4A or CYP2E1 expression. Straight-chain saturated fatty acids, C8 to C16, increased levels of CYP2B and CYP4A mRNA, but not CYP2E1 mRNA. Treatment with octanoylcarnitine, a mitochondrial β-oxidation inhibitor, in combination with hexadecanoate increased CYP2B and CYP4A expression ∼1.4-fold over that observed with hexadecanoate alone, suggesting that mitochondrial conversion of fatty acids to Ketone Bodies was not required for enhanced CYP2B expression and that mitochondrial β-oxidation decreased intracellular fatty acid levels and thereby lowered CYP2B expression. Undecynoic acid or aminobenzotriazole treatment increased CYP2B mRNA levels, consistent with these compounds inhibiting the initial CYP4A-catalyzed step in the conversion of monocarboxylic to dicarboxylic acids and thereby decreasing peroxisomal β-oxidation and increasing intracellular fatty acid levels. Addition of glycerol, which suppresses fatty acid synthesis by inhibiting conversion of lactate to pyruvate, decreased basal expression of CYP2B and CYP4A but did not alter CYP2E1 expression. Pyruvate, but not lactate, completely prevented the glycerol-mediated decrease in CYP2B expression. These results provide evidence that intracellular levels of fatty acids and Ketone Bodies regulate the expression of CYP2B but not CYP2E1.
