β-Hydroxybutyrate: A signaling metabolite in starvation response?

doi:10.1016/j.cellsig.2016.04.005

Cellular Signalling

Volume 28, Issue 8, August 2016, Pages 917-923

https://doi.org/10.1016/j.cellsig.2016.04.005 Get rights and content

Highlights

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β-Hydroxybutyrate sustains energetic requirement during starvation.
•
β-Hydroxybutyrate has signaling functions.
•
β-Hydroxybutyrate regulates nutrient utilization and energy expenditure.
•
β-Hydroxybutyrate might function as a signaling metabolite in starvation response.

Abstract

Ketone bodies β-hydroxybutyrate (BHB) and acetoacetate are important metabolic substrates for energy production during prolonged fasting. However, BHB also has signaling functions. Through several metabolic pathways or processes, BHB modulates nutrient utilization and energy expenditure. These findings suggest that BHB is not solely a metabolic intermediate, but also acts as a signal to regulate metabolism and maintain energy homeostasis during nutrient deprivation. We briefly summarize the metabolism and emerging physiological functions of ketone bodies and highlight the potential role for BHB as a signaling molecule in starvation response.

Graphical abstract

Introduction

Starvation is a common challenge in nature and organisms have evolved sophisticated mechanisms to survive periods of food scarcity [1]. Metabolic adaptation is probably the most important obligated event that occurs in nutrient deprivation conditions and encompasses a series of profound changes at the behavioral, physiological and biochemical levels designed to maintain energy homeostasis by suppressing energy-consuming processes, such as growth and reproduction, while preserving basal metabolic functions [1], [2].

In mammals, the liver plays a fundamental role in metabolism by coordinating metabolic signals and energy substrates from and within peripheral tissues. For example, when the blood-glucose level drops as during food deprivation the liver generates glucose by breaking down glycogen stores, and through gluconeogenesis [3]. Furthermore, when low blood-glucose persists, the liver synthesizes ketone bodies as metabolic fuels for extrahepatic tissues [4].

Ketone bodies, namely β-hydroxybutyrate (BHB) and acetoacetate (AcAc), are small molecules that play central role in energy homeostasis in almost all living organisms [5]. In mammals, by connecting fat stores in adipocytes to adenosine triphosphate (ATP) production in peripheral tissues, these metabolic intermediates sustain energetic requirements for basic cellular functions during starvation periods [6]. In addition, ketone bodies are also produced during exercise, the neonatal period, uncontrolled diabetes or feeding a low-carbohydrate, high-fat ketogenic diet. Today, although a lot of investigations have revealed the molecular mechanisms of ketone body metabolism and its regulation, we know very little about the real biological significance of these molecules in cellular homeostasis.

Section snippets

Ketone body metabolism

Ketogenesis, the synthesis of ketone bodies (Fig. 1), occurs within the mitochondrial matrix and begins with the condensation of β-oxidation-derived acetyl-coenzyme A (acetyl-CoA) into the ketone body AcAc by the sequential requirement of mitochondrial enzymes 3-hydroxy-3-methylglutaryl CoA synthase 2 (HGMCS2) and 3-hydroxy-3-methylglutaryl CoA lyase (HMGCL). Then, AcAc can be spontaneously converted into acetone, another ketone body that does not have any metabolic function, or into BHB by BHB

Signaling functions of β-hydroxybutyrate

An increasing number of metabolites–e.g., lactate, succinate, and α-ketoglutarate; and the dietary gut microbial short-chain fatty acids (SCFAs) butyrate, propionate, and acetate–have been shown to activate downstream signaling pathways by acting through G protein-coupled receptors (GPCRs) in distinct organs and tissues to regulate whole-body energy metabolism [12], [13], [14], [15]. Similarly, it has become increasingly clear during the last years that BHB is not only a simple energy

Concluding remarks and future directions

Metabolic adaptation relies on major processes and pathways required for organismal survival during food deprivation and in this situation ketone bodies play a central role in energy homeostasis. BHB has a well-recognized role in metabolism, however, several pieces of evidence indicate that this molecule is implicated in a wide variety of processes and has signaling functions. For example, at the cell surface BHB, as a hormone-like molecule, binds to extracellular receptors to regulate

Acknowledgements

We thank members of the Pedraza-Chaverri laboratory for helpful suggestions and discussions. CONACYT 220046 and 252008 grants supported this work.

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Reviewβ-Hydroxybutyrate: A signaling metabolite in starvation response?

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Ketone body metabolism

Signaling functions of β-hydroxybutyrate

Concluding remarks and future directions

Acknowledgements

Comp. Biochem. Physiol. A Mol. Integr. Physiol.

J. Biol. Chem.

Mol. Metab.

Trends Endocrinol. Metab.

Diabetes Res. Clin. Pract.

J. Biol. Chem.

Exp. Neurol.

Biochem. Biophys. Res. Commun.

Jpn. J. Pharmacol.

Cell Metab.

Cell Metab.

J. Biol. Chem.

FEBS Lett.

Biochem. Biophys. Res. Commun.

Mol. Cell

Trends Cell Biol.

Cell Metab.

Nutrition

Cell Metab.

Cell Metab.

Dev. Cell

FEBS Lett.

J. Clin. Invest.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Neuroinflammation

Immunity

Rev. Endocr. Metab. Disord.

Trends Endocrinol. Metab.

Appetite

The comparative physiology of food deprivation: from feast to famine

Annu. Rev. Physiol.

Energy metabolism in the liver

Compr. Physiol.

Physiological roles of ketone bodies as substrates and signals in mammalian tissues

Physiol. Rev.

Role of beta-hydroxybutyrate, its polymer poly-beta-hydroxybutyrate and inorganic polyphosphate in mammalian health and disease

Front. Physiol.

Fuel metabolism in starvation

Annu. Rev. Nutr.

Ketone body metabolism and cardiovascular disease

Am. J. Physiol. Heart Circ. Physiol.

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

J. Clin. Invest.

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

Am. J. Physiol. Endocrinol. Metab.

G protein-coupled receptors for energy metabolites as new therapeutic targets

Nat. Rev. Drug Discov.

Essential roles of four-carbon backbone chemicals in the control of metabolism

World J. Biol. Chem.

Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation

Nutrients

Short-chain fatty acids in control of body weight and insulin sensitivity

Nat. Rev. Endocrinol.

Acetoacetate accelerates muscle regeneration and ameliorates muscular dystrophy in mice

J. Biol. Chem.

Short-chain fatty acids and ketones directly regulate sympathetic nervous system via H protein-coupled receptor 41 (GRP41)

Proc. Natl. Acad. Sci. U. S. A.

Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor

Science

The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease

Nat. Med.

d-Beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease

J. Clin. Invest.

Ketone bodies are protective against oxidative stress in neocortical neurons

J. Neurochem.

Review
β-Hydroxybutyrate: A signaling metabolite in starvation response?