Regulation Of Ketone Body Metabolism And The Role Of Pparα
1. Introduction Adaptation to limited nutritional resources in the environment requires the development of mechanisms that enable temporal functioning in a state of energy deficiency at both systemic and cellular levels. Different molecular and cellular mechanisms have evolved allowing survival during nutrient insufficiency. Some rely on the decrease of metabolic rates, body temperature, or even shutting down most of the live functions during deep hibernation, aestivation or brumation. Other strategies require development of metabolic flexibility and effective fuel management. Peroxisome Proliferator Activated Receptors (PPARs) are important regulators of cellular responses to variable nutrient supply during both fed and fasted states. Acting as transcription factors, and directly modulated by fatty acids and their derivatives, PPARs induce transcription of the proper set of genes, encoding proteins and enzymes indispensable for lipid, amino acid and carbohydrate metabolism. In this review, we make an attempt to outline the regulation of ketone body synthesis and utilization in normal and transformed cells, as well as summarize the role of PPARα in these processes. 2. Ketogenesis and Ketolysis Metabolic adaptation to prolonged fasting in humans is based both on coordinated responses of vital organs, mainly liver, kidneys and muscles, and on restoring nutritional preferences at the cellular level. In the fed state, cells primarily rely on glucose metabolism, whereas during longer food deprivation blood glucose levels drop because glycogen reserves are only sufficient for less than a day. In such conditions, glucose is spared mainly for neurons, but also for erythrocytes and proliferating cells in bone marrow or those involved in tissue regeneration. The most important c Continue reading >>
Understanding Ketosis
To gain a better understanding of ketosis and the ketogenic diet, it is important to take a look at the physiology behind the diet. If you recall from the article What is a Ketogenic Diet? the goal of a ketogenic diet is to induce ketosis by increasing ketone body production. A key step in understanding the diet is to learn what ketosis is, what are ketones and what do they do. “Normal” Metabolism Learning the basics of the various metabolic processes of the body will better your ability to understand ketosis. Under the normal physiological conditions that are common today, glucose is our body’s primary source of energy. Following ingestion, carbohydrates are broken down into glucose and released into the blood stream. This results in the release of insulin from the pancreas. Insulin not only inhibits fat oxidation but also acts as a key holder for cells by allowing glucose from the blood to be shuttled into cells via glucose transporters (GLUT). The amount of insulin required for this action varies between individuals depending on their insulin sensitivity. Once inside the cell, glucose undergoes glycolysis, a metabolic process that produces pyruvate and energy in the form of adenosine triphosphate (ATP). Once pyruvate is formed as an end product of glycolysis, it is shuttled into the mitochondria, where it is converted to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA then enters the TCA cycle to produce additional energy with the aid of the electron transport chain. Since glucose is so rapidly metabolized for energy production and has a limited storage capacity, other energy substrates, such as fat, get stored as triglycerides due to our body’s virtually infinite fat storage capacity. When a sufficient source of carbohydrates is not available, the body adap Continue reading >>
Ketone Bodies As Signaling Metabolites
Outline of ketone body metabolism and regulation. The key irreversible step in ketogenesis is synthesis of 3-hydroxy-3-methylglutaryl-CoA by HMGCS2. Conversely, the rate limiting step in ketolysis is conversion of acetoacetate to acetoacetyl-CoA by OXCT1. HMGCS2 transcription is heavily regulated by FOXA2, mTOR, PPARα, and FGF21. HMGCS2 activity is post-translationally regulated by succinylation and acetylation/SIRT3 deacetylation. Other enzymes are regulated by cofactor availability (e.g., NAD/NADH2 ratio for BDH1). All enzymes involved in ketogenesis are acetylated and contain SIRT3 deacetylation targets, but the functional significance of this is unclear other than for HMGCS2. Although ketone bodies are thought to diffuse across most plasma membranes, the transporter SLC16A6 may be required for liver export, whereas several monocarboxylic acid transporters assist with transport across the blood–brain barrier. Abbreviations: BDH1, β-hydroxybutyrate dehydrogenase; FGF21, fibroblast growth factor 21; FOXA2, forkhead box A2; HMGCS2, 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase 2; HMGCL, HMG-CoA lyase; MCT1/2, monocarboxylic acid transporters 1/2; mTOR, mechanistic target of rapamycin; OXCT1, succinyl-CoA:3-ketoacid coenzyme A transferase; PPARα, peroxisome proliferator-activated receptor α; SIRT3, sirtuin 3; SLC16A6, solute carrier family 16 (monocarboxylic acid transporter), member 6; TCA cycle, tricarboxylic acid cycle. Continue reading >>
Ketone Bodies Metabolism During Ischemic And Reperfusion Brain Injuries Following Bilateral Occlusion Of Common Carotid Arteries In Rats
ORIGINAL ARTICLE Metabolismo dos corpos cetônicos durante as lesões de isquemia e reperfusão cerebrais após oclusão bilateral das artérias carótidas comuns em ratos Mário Henrique Girão FariaI; Luis Roberto Franklin MunizII; Paulo Roberto Leitão de VasconcelosIII IMD, Fellow PhD degree, Department of Physiology and Pharmacology, Federal University of Ceará Medical School, Brazil IIMD, Neurosurgeon, Dr. José Frota Institute (IJF), Fortaleza, Ceará, Brazil IIIPhD, Associate Professor, Coordinator of Post-Graduation Program in Surgery, Department of Surgery, Federal University of Ceará Medical School, Brazil ABSTRACT PURPOSE: To evaluate the in vivo alterations on ketone bodies metabolism after cerebral ischemia/reperfusion through an experimental model of brain ischemia induced by simple occlusion of common carotid arteries (CCAs) in Wistar rats. METHODS: Forty-eight male Wistar rats were randomly distributed on two groups (S – Sham; T – Test) and further redistributed into four times sets of study. After bilateral occlusion of CCAs for 30min, the animals of group T were allowed reperfusion for 0, 5, 10 and 15min. Samples of cerebral tissue and systemic arterial blood were collected and the metabolites acetoacetate (ACT) and beta-hydroxybutyrate (BHB) were determined. RESULTS: Cerebral ACT and BHB levels increased significantly in Group T after 30min of carotid occlusion (time 0). The highest brain ketone bodies (ACT+BHB) concentration was verified at 5min of reperfusion, decreasing after 10min of recirculation. Systemic ketone bodies levels increased similarly between test and sham groups. Group S demonstrated a significant increase in cerebral and systemic ACT and BHB concentrations mainly after 40-45min of study. CONCLUSIONS: The partial transient acu Continue reading >>
Regulation Of Hypothalamic Neuronal Sensing And Food Intake By Ketone Bodies And Fatty Acids
Metabolic sensing neurons in the ventromedial hypothalamus (VMH) alter their activity when ambient levels of metabolic substrates, such as glucose and fatty acids (FA), change. To assess the relationship between a high-fat diet (HFD; 60%) intake on feeding and serum and VMH FA levels, rats were trained to eat a low-fat diet (LFD; 13.5%) or an HFD in 3 h/day and were monitored with VMH FA microdialysis. Despite having higher serum levels, HFD rats had lower VMH FA levels but ate less from 3 to 6 h of refeeding than did LFD rats. However, VMH β-hydroxybutyrate (β-OHB) and VMH-to-serum β-OHB ratio levels were higher in HFD rats during the first 1 h of refeeding, suggesting that VMH astrocyte ketone production mediated their reduced intake. In fact, using calcium imaging in dissociated VMH neurons showed that ketone bodies overrode normal FA sensing, primarily by exciting neurons that were activated or inhibited by oleic acid. Importantly, bilateral inhibition of VMH ketone production with a 3-hydroxy-3-methylglutaryl-CoA synthase inhibitor reversed the 3- to 6-h HFD-induced inhibition of intake but had no effect in LFD-fed rats. These data suggest that a restricted HFD intake regimen inhibits caloric intake as a consequence of FA-induced VMH ketone body production by astrocytes. Several lines of evidence support the idea that food intake can be altered by ingestion of a high-fat diet (HFD) (1–5). Prolonged intraventricular infusion of the long-chain fatty acid (LCFA), oleic acid (OA), causes a decrease in intake (6). However, the physiological significance of such effects on feeding can be questioned, as can those of direct infusions of fatty acid (FA) into brain areas such as the hypothalamus (7). A major problem is that there is no current information about how brai Continue reading >>
Ketone Body Metabolism
Ketone body metabolism includes ketone body synthesis (ketogenesis) and breakdown (ketolysis). When the body goes from the fed to the fasted state the liver switches from an organ of carbohydrate utilization and fatty acid synthesis to one of fatty acid oxidation and ketone body production. This metabolic switch is amplified in uncontrolled diabetes. In these states the fat-derived energy (ketone bodies) generated in the liver enter the blood stream and are used by other organs, such as the brain, heart, kidney cortex and skeletal muscle. Ketone bodies are particularly important for the brain which has no other substantial non-glucose-derived energy source. The two main ketone bodies are acetoacetate (AcAc) and 3-hydroxybutyrate (3HB) also referred to as β-hydroxybutyrate, with acetone the third, and least abundant. Ketone bodies are always present in the blood and their levels increase during fasting and prolonged exercise. After an over-night fast, ketone bodies supply 2–6% of the body's energy requirements, while they supply 30–40% of the energy needs after a 3-day fast. When they build up in the blood they spill over into the urine. The presence of elevated ketone bodies in the blood is termed ketosis and the presence of ketone bodies in the urine is called ketonuria. The body can also rid itself of acetone through the lungs which gives the breath a fruity odour. Diabetes is the most common pathological cause of elevated blood ketones. In diabetic ketoacidosis, high levels of ketone bodies are produced in response to low insulin levels and high levels of counter-regulatory hormones. Ketone bodies The term ‘ketone bodies’ refers to three molecules, acetoacetate (AcAc), 3-hydroxybutyrate (3HB) and acetone (Figure 1). 3HB is formed from the reduction of AcAc i Continue reading >>
Nutrition Chapter 7
Sort Which of the following is a characteristic of the metabolism of specific macronutrients? a. The rate of fat oxidation does not change when fat is eaten in excess b. The rate of protein oxidation does not change when protein is eaten in excess c. The rate of glucose oxidation does not change when carbohydrate is eaten in excess d. The conversion of dietary glucose to fat represents the major pathway of carbohydrate utilization Which of the following is a characteristic of the metabolism of specific macronutrients? a. The rate of fat oxidation does not change when fat is eaten in excess b. The rate of protein oxidation does not change when protein is eaten in excess c. The rate of glucose oxidation does not change when carbohydrate is eaten in excess d. The conversion of dietary glucose to fat represents the major pathway of carbohydrate utilization the rate of fat oxidation does not change when fat is eaten in excess All of the following are features of the metabolism of surplus dietary carbohydrate in human beings except a. excess glucose suppresses fat oxidation. b. excess glucose is oxidized only very slowly. c. excess glucose is first used to fill glycogen reserves. d. conversion of excess glucose to fat occurs only to a very limited extent. All of the following are features of the metabolism of surplus dietary carbohydrate in human beings except a. excess glucose suppresses fat oxidation. b. excess glucose is oxidized only very slowly. c. excess glucose is first used to fill glycogen reserves. d. conversion of excess glucose to fat occurs only to a very limited extent. excess glucose is oxidized only very slowly Which of the following is a feature of the metabolism of surplus dietary fat? a. Excess fat is almost all stored b. Excess fat promotes increased fat o Continue reading >>
The Clinical Significance Of The Arterial Ketone Body Ratio As An Early Indicator Of Graft Viability In Human Liver Transplantation1,2
Several parameters have been proposed for the prediction of liver graft failure, such as the levels of hepatic enzymes, serum bilirubin, plasma amino acids, and biopsy findings (1, 2), but none can forecast graft recovery until the patient’s condition becomes critical. As a step toward this objective, an interinstitutional study was undertaken between Kyoto University and the University of Pittsburgh. The Kyoto team has quantified derangements of hepatic energy metabolism after cirrhotic liver resection, liver transplantation, and other disease states (3–5). The redox potential (reduction-oxidation potential) of hepatic mitochondria is one of the fundamental regulatory factors of the liver metabolism, and can be assessed by measuring the ketone body ratio in the arterial blood (AKBR)* of patients (3). The AKBR is closely correlated with the energy charge level of the liver in jaundice, massive hemorrhage, experimental liver transplantation, and after hepatic resection (6–8). After liver transplantation, patients with well-functioning grafts usually recover from the stress of the operation quickly and uneventfully, and can be discharged within one or 2 days from the intensive care unit (ICU). In contrast, there is extreme morbidity and mortality in patients whose new livers do not resume function promptly, whose grafts fail secondarily because of rejection or technical accidents, and whose grafts are secondarily damaged after renal or cardiopulmonary complications (9). Accurate prediction of the fate of these hepatic grafts is an important objective. The Hannover liver group proposed the metabolic assessment of transplanted liver allografts with AKBR as a parameter (10, 11). They showed that an AKBR below 0.7 at 24 hr after organ recirculation was an early predicto Continue reading >>
Diabetes With Ketone Bodies In Dogs
Studies show that female dogs (particularly non-spayed) are more prone to DKA, as are older canines. Diabetic ketoacidosis is best classified through the presence of ketones that exist in the liver, which are directly correlated to the lack of insulin being produced in the body. This is a very serious complication, requiring immediate veterinary intervention. Although a number of dogs can be affected mildly, the majority are very ill. Some dogs will not recover despite treatment, and concurrent disease has been documented in 70% of canines diagnosed with DKA. Diabetes with ketone bodies is also described in veterinary terms as diabetic ketoacidosis or DKA. It is a severe complication of diabetes mellitus. Excess ketone bodies result in acidosis and electrolyte abnormalities, which can lead to a crisis situation for your dog. If left in an untreated state, this condition can and will be fatal. Some dogs who are suffering from diabetic ketoacidosis may present as systemically well. Others will show severe illness. Symptoms may be seen as listed below: Change in appetite (either increase or decrease) Increased thirst Frequent urination Vomiting Abdominal pain Mental dullness Coughing Fatigue or weakness Weight loss Sometimes sweet smelling breath is evident Slow, deep respiration. There may also be other symptoms present that accompany diseases that can trigger DKA, such as hypothyroidism or Cushing’s disease. While some dogs may live fairly normal lives with this condition before it is diagnosed, most canines who become sick will do so within a week of the start of the illness. There are four influences that can bring on DKA: Fasting Insulin deficiency as a result of unknown and untreated diabetes, or insulin deficiency due to an underlying disease that in turn exacerba Continue reading >>
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. Notes Philippe Pinckaers, Tyler Churchward-Venne, David Bailey, and Luc van Loon declare that they have no conflicts of interest relevant to the content of this review. Continue reading >>
Ketone Body Infusion With 3‐hydroxybutyrate Reduces Myocardial Glucose Uptake And Increases Blood Flow In Humans: A Positron Emission Tomography Study
Background High levels of ketone bodies are associated with improved survival as observed with regular exercise, caloric restriction, and—most recently—treatment with sodium–glucose linked transporter 2 inhibitor antidiabetic drugs. In heart failure, indices of ketone body metabolism are upregulated, which may improve energy efficiency and increase blood flow in skeletal muscle and the kidneys. Nevertheless, it is uncertain how ketone bodies affect myocardial glucose uptake and blood flow in humans. Our study was therefore designed to test whether ketone body administration in humans reduces myocardial glucose uptake (MGU) and increases myocardial blood flow. Methods and Results Eight healthy subjects, median aged 60 were randomly studied twice: (1) During 390 minutes infusion of Na‐3‐hydroxybutyrate (KETONE) or (2) during 390 minutes infusion of saline (SALINE), together with a concomitant low‐dose hyperinsulinemic–euglycemic clamp to inhibit endogenous ketogenesis. Myocardial blood flow was measured by 15O‐H2O positron emission tomography/computed tomography, myocardial fatty acid metabolism by 11C‐palmitate positron emission tomography/computed tomography and MGU by 18F‐fluorodeoxyglucose positron emission tomography/computed tomography. Similar euglycemia, hyperinsulinemia, and suppressed free fatty acids levels were recorded on both study days; Na‐3‐hydroxybutyrate infusion increased circulating Na‐3‐hydroxybutyrate levels from zero to 3.8±0.5 mmol/L. MGU was halved by hyperketonemia (MGU [nmol/g per minute]: 304±97 [SALINE] versus 156±62 [KETONE], P<0.01), whereas no effects were observed on palmitate uptake oxidation or esterification. Hyperketonemia increased heart rate by ≈25% and myocardial blood flow by 75%. Conclusions Ketone Continue reading >>
Ketone Bodies
Ketone bodies Acetone Acetoacetic acid (R)-beta-Hydroxybutyric acid Ketone bodies are three water-soluble molecules (acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone) that are produced by the liver from fatty acids[1] during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, prolonged intense exercise,[2], alcoholism or in untreated (or inadequately treated) type 1 diabetes mellitus. These ketone bodies are readily picked up by the extra-hepatic tissues, and converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy.[3] In the brain, ketone bodies are also used to make acetyl-CoA into long-chain fatty acids. Ketone bodies are produced by the liver under the circumstances listed above (i.e. fasting, starving, low carbohydrate diets, prolonged exercise and untreated type 1 diabetes mellitus) as a result of intense gluconeogenesis, which is the production of glucose from non-carbohydrate sources (not including fatty acids).[1] They are therefore always released into the blood by the liver together with newly produced glucose, after the liver glycogen stores have been depleted (these glycogen stores are depleted after only 24 hours of fasting)[1]. When two acetyl-CoA molecules lose their -CoAs, (or Co-enzyme A groups) they can form a (covalent) dimer called acetoacetate. Beta-hydroxybutyrate is a reduced form of acetoacetate, in which the ketone group is converted into an alcohol (or hydroxyl) group (see illustration on the right). Both are 4-carbon molecules, that can readily be converted back into acetyl-CoA by most tissues of the body, with the notable exception of the liver. Acetone is the decarboxylated form of acetoacetate which cannot be converted Continue reading >>
Hypothalamic Sensing Of Ketone Bodies After Prolonged Cerebral Exposure Leads To Metabolic Control Dysregulation
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. Energy homeostasis can be maintained by the activation of several mechanisms involving an interplay between the central nervous system (CNS) and peripheral organs. Among the different parameters regulated to maintain energy supply and expenditure on balance, body weight and glycemia are normally kept constant. This balance is due to different circulating or nervous signals allowing peripheral organs to communica Continue reading >>
What Is Betahydroxybutyrate Or Bhb?
[et_pb_section bb_built=”1″ admin_label=”section” padding_mobile=”off” _builder_version=”3.0.47″ custom_padding_tablet=”50px|0|50px|0″ custom_padding_last_edited=”on|desktop”][et_pb_row admin_label=”row” padding_mobile=”off” column_padding_mobile=”on” _builder_version=”3.0.47″ background_size=”initial” background_position=”top_left” background_repeat=”repeat”][et_pb_column type=”4_4″][et_pb_text _builder_version=”3.0.89″ background_size=”initial” background_position=”top_left” background_repeat=”repeat”] Beta…hydro…what? Technical and “science-y” words can be super intimidating, but we’re here to break down one of the top words in the ketogenic diet community — betahydroxybutryate (or BHB). We’ll chat all about what BHB is, why you’d want to use it for energy, and all about side effects and benefits. Beta-hydroxybutyrate, or simply BHB, is a molecule that is considered a ketone body. It is one of the main molecules that helps your body produce energy in the absence of glucose. This molecule is essential if you using your own fat for fuel, or taking BHB as a supplement to increase energy production — essentially to be in nutritional ketosis. If you’re not certain about what ketones are or what nutritional ketosis is, you should back up a little bit and read more about that here. Technically speaking, beta-hydroxybutyrate is NOT a ketone body. Ketone bodies, or ketones are technically carbonyl carbons who are bonded to two additional carbons atoms. One carbon has four available bonds, double bonded to oxygen and two single bonds to carbon, we have a ketone. If you have a carbon atom that is double bonded to an oxygen (carbonyl group), which is also bound to an -OH group instead of Continue reading >>
Fenofibrate Induces Ketone Body Production In Melanoma And Glioblastoma Cells
1Department of Food Biotechnology, Faculty of Food Technology, University of Agriculture, Krakow, Poland 2Molecular and Metabolic Oncology Program, Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA 3Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland 4Neurological Cancer Research, Stanley S Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA Ketone bodies [beta-hydroxybutyrate (bHB) and acetoacetate] are mainly produced in the liver during prolonged fasting or starvation. bHB is a very efficient energy substrate for sustaining ATP production in peripheral tissues; importantly, its consumption is preferred over glucose. However, the majority of malignant cells, particularly cancer cells of neuroectodermal origin such as glioblastoma, are not able to use ketone bodies as a source of energy. Here, we report a novel observation that fenofibrate, a synthetic peroxisome proliferator-activated receptor alpha (PPARa) agonist, induces bHB production in melanoma and glioblastoma cells, as well as in neurospheres composed of non-transformed cells. Unexpectedly, this effect is not dependent on PPARa activity or its expression level. The fenofibrate-induced ketogenesis is accompanied by growth arrest and downregulation of transketolase, but the NADP/NADPH and GSH/GSSG ratios remain unaffected. Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma. Continue reading >>
