Metabolic and Signaling Roles of Ketone Bodies in Health and Disease

2021 ◽  
Vol 41 (1) ◽  
pp. 49-77
Author(s):  
Patrycja Puchalska ◽  
Peter A. Crawford
Keyword(s):  
Ketone Body ◽  
Energy Homeostasis ◽  
Ketone Bodies ◽  
Pharmacological Interventions ◽  
Specific Effects ◽  
Redox Partners ◽  
Low Carbohydrate ◽  
Organ Specific ◽  
Health And Disease ◽  
Cell Type Specific

Ketone bodies play significant roles in organismal energy homeostasis, serving as oxidative fuels, modulators of redox potential, lipogenic precursors, and signals, primarily during states of low carbohydrate availability. Efforts to enhance wellness and ameliorate disease via nutritional, chronobiological, and pharmacological interventions have markedly intensified interest in ketone body metabolism. The two ketone body redox partners, acetoacetate and D-β-hydroxybutyrate, serve distinct metabolic and signaling roles in biological systems. We discuss the pleiotropic roles played by both of these ketones in health and disease. While enthusiasm is warranted, prudent procession through therapeutic applications of ketogenic and ketone therapies is also advised, as a range of metabolic and signaling consequences continue to emerge. Organ-specific and cell-type-specific effects of ketone bodies are important to consider as prospective therapeutic and wellness applications increase.

scholarly journals Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice

2016 ◽  
Vol 310 (2) ◽  
pp. E103-E115 ◽  
Author(s):  
Lionel Carneiro ◽  
Sarah Geller ◽  
Xavier Fioramonti ◽  
Audrey Hébert ◽  
Cendrine Repond ◽  
...  
Keyword(s):  
Food Intake ◽  
Ketone Body ◽  
Energy Homeostasis ◽  
Ketone Bodies ◽  
Glucose Production ◽  
Body Level ◽  
Homeostasis Regulation ◽  
The Impact ◽  
Body Concentration

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.

scholarly journals Ketone Body Metabolism in the Ischemic Heart

2021 ◽  
Vol 8 ◽  
Author(s):  
Stephen C. Kolwicz
Keyword(s):  
Ketone Body ◽  
Ketone Bodies ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Myocardial Infarctions ◽  
Ketogenic Diets ◽  
Health And Disease ◽  
Ketone Body Metabolism ◽  
Artery Disease ◽  
Fuel Source

Ketone bodies have been identified as an important, alternative fuel source in heart failure. In addition, the use of ketone bodies as a fuel source has been suggested to be a potential ergogenic aid for endurance exercise performance. These findings have certainly renewed interest in the use of ketogenic diets and exogenous supplementation in an effort to improve overall health and disease. However, given the prevalence of ischemic heart disease and myocardial infarctions, these strategies may not be ideal for individuals with coronary artery disease. Although research studies have clearly defined changes in fatty acid and glucose metabolism during ischemia and reperfusion, the role of ketone body metabolism in the ischemic and reperfused myocardium is less clear. This review will provide an overview of ketone body metabolism, including the induction of ketosis via physiological or nutritional strategies. In addition, the contribution of ketone body metabolism in healthy and diseased states, with a particular emphasis on ischemia-reperfusion (I-R) injury will be discussed.

scholarly journals Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation

2013 ◽  
Vol 304 (4) ◽  
pp. E363-E374 ◽  
Author(s):  
David G. Cotter ◽  
Rebecca C. Schugar ◽  
Anna E. Wentz ◽  
D. André d'Avignon ◽  
Peter A. Crawford
Keyword(s):  
Ketone Body ◽  
Neonatal Period ◽  
Ketone Bodies ◽  
Fatty Acyl ◽  
Carbohydrate Intake ◽  
Tissue Specific ◽  
Neonatal Mice ◽  
Coa Transferase ◽  
Low Carbohydrate ◽  
Ketone Body Metabolism

During states of low carbohydrate intake, mammalian ketone body metabolism transfers energy substrates originally derived from fatty acyl chains within the liver to extrahepatic organs. We previously demonstrated that the mitochondrial enzyme coenzyme A (CoA) transferase [succinyl-CoA:3-oxoacid CoA transferase (SCOT), encoded by nuclear Oxct1] is required for oxidation of ketone bodies and that germline SCOT-knockout (KO) mice die within 48 h of birth because of hyperketonemic hypoglycemia. Here, we use novel transgenic and tissue-specific SCOT-KO mice to demonstrate that ketone bodies do not serve an obligate energetic role within highly ketolytic tissues during the ketogenic neonatal period or during starvation in the adult. Although transgene-mediated restoration of myocardial CoA transferase in germline SCOT-KO mice is insufficient to prevent lethal hyperketonemic hypoglycemia in the neonatal period, mice lacking CoA transferase selectively within neurons, cardiomyocytes, or skeletal myocytes are all viable as neonates. Like germline SCOT-KO neonatal mice, neonatal mice with neuronal CoA transferase deficiency exhibit increased cerebral glycolysis and glucose oxidation, and, while these neonatal mice exhibit modest hyperketonemia, they do not develop hypoglycemia. As adults, tissue-specific SCOT-KO mice tolerate starvation, exhibiting only modestly increased hyperketonemia. Finally, metabolic analysis of adult germline Oxct1+/− mice demonstrates that global diminution of ketone body oxidation yields hyperketonemia, but hypoglycemia emerges only during a protracted state of low carbohydrate intake. Together, these data suggest that, at the tissue level, ketone bodies are not a required energy substrate in the newborn period or during starvation, but rather that integrated ketone body metabolism mediates adaptation to ketogenic nutrient states.

scholarly journals Mapping the Endogenous Ketogenic System Across Ages, Sex and Diets

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 982-982
Author(s):  
Brenda Eap ◽  
Mitsunori Nomura ◽  
Oishika Panda ◽  
Thelma Garcia ◽  
John Newman
Keyword(s):  
Ketone Body ◽  
Energy Homeostasis ◽  
Ketone Bodies ◽  
Primary Energy ◽  
Normal Diet ◽  
Compensatory Response ◽  
Age Related ◽  
Body Production ◽  
Beta Hydroxybutyrate ◽  
Ketone Ester

Abstract Understanding how our cells maintain energy homeostasis has long been a focus of aging biology. A decline in energy metabolism is central to many age-related diseases such as Alzheimer’s disease, heart failure, frailty, and delirium. Intervening on pathways involved in energy homeostasis can extend healthy lifespan. When our primary energy substrate glucose, is scarce, our bodies use ketone bodies (i.e. beta-hydroxybutyrate, acetoacetate, acetone). Aging is associated with glucose intolerance and insulin insensitivity, yet what role ketone body metabolism might play in compensating for impaired glucose utilization in age-related diseases is understudied. Here, we investigated how the body’s endogenous ketone body production and utilization pathways are modulated by age across the lifespan of female and male C57BL/6 mice (4 mo old, 12 mo old, 22 mo old). We show how different ages have different metabolic and gene expression responses to 1-week ketogenic diet (KD) or ketone ester diet. We observed an apparently compensatory ketogenic response in older animals fed normal diet, with a stronger compensatory response driven by KD. We observed tissue-specific changes, including induction of ketone body production enzymes in the aging heart. When comparing the ketogenic capacity between sexes, females had a higher basal level and less variation with age, underscoring the importance of sexual dimorphism in metabolism. Overall, these findings suggest that older animals use ketone bodies to meet energetic demands in a normal diet context. This study supports the potential roles of ketogenic therapies such as exogenous ketones to improve energy homeostasis in conditions of aging.

Increased Production of Nitric Oxide Mediates Selective Organ-Specific Effects of Endotoxin on Oxidative Stress

2012 ◽  
Vol 11 (2) ◽  
pp. 161-172 ◽  
Author(s):  
Seyhan Sahan-Firat ◽  
Necmiye Canacankatan ◽  
Belma Korkmaz ◽  
Hatice Yildirim ◽  
Lulufer Tamer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Specific Effects ◽  
Organ Specific

scholarly journals Ketone body 3-hydroxybutyrate as a biomarker of aggression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. M. Whipp ◽  
E. Vuoksimaa ◽  
T. Korhonen ◽  
R. Pool ◽  
A. But ◽  
...  
Keyword(s):  
Young Adults ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Population Based ◽  
Resonance Spectroscopy ◽  
Linear Regression Models ◽  
Complex Behaviour ◽  
Replication Sample ◽  
Discovery Sample ◽  
Independent Replication

AbstractHuman aggression is a complex behaviour, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983–1987, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the response variable and aggression ratings as predictor variables, and included several potential confounders. All metabolites showed low correlations with aggression, with only one—3-hydroxybutyrate, a ketone body produced during fasting—showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated (age 14) aggression were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher aggression (self-rated) was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.

scholarly journals Cell type-specific effects ofYersinia pseudotuberculosisvirulence effectors

2009 ◽  
Vol 11 (12) ◽  
pp. 1750-1767 ◽  
Author(s):  
Anna Fahlgren ◽  
Linda Westermark ◽  
Karen Akopyan ◽  
Maria Fällman
Keyword(s):  
Cell Type ◽  
Specific Effects ◽  
Cell Type Specific

scholarly journals The thymus and the science of self

2021 ◽  
Author(s):  
Vincent Geenen
Keyword(s):  
T Cells ◽  
Adaptive Immune System ◽  
Lymphoid Organ ◽  
The Body ◽  
Effector Cells ◽  
Major Organ ◽  
Organ Specific ◽  
Health And Disease ◽  
Essential State ◽  
The 1960S

AbstractThe conventional perception asserts that immunology is the science of ‘discrimination’ between self and non-self. This concept is however no longer tenable as effector cells of the adaptive immune system are first conditioned to be tolerant to the body’s own antigens, collectively known as self until now. Only then attain these effectors the responsiveness to non-self. The acquisition of this essential state of tolerance to self occurs for T cells in the thymus, the last major organ of our body that revealed its intricate function in health and disease. The ‘thymus’ as an anatomical notion was first notably documented in Ancient Greece although our present understanding of the organ’s functions was only deciphered commencing in the 1960s. In the late 1980s, the thymus was identified as the site where clones of cells reactive to self, termed ‘forbidden’ thymocytes, are physically depleted as the result of a process now known as negative selection. The recognition of this mechanism further contributed to the belief that the central rationale of immunology as a science lies in the distinction between self and non-self. This review will discuss the evidence that the thymus serves as a unique lymphoid organ able to instruct T cells to recognize and be tolerant to harmless self before adopting the capacity to defend the body against potentially injurious non-self-antigens presented in the context of different challenges from infections to exposure to malignant cells. The emerging insight into the thymus’ cardinal functions now also provides an opportunity to exploit this knowledge to develop novel strategies that specifically prevent or even treat organ-specific autoimmune diseases.

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