Tier 2 · Peer-reviewed secondaryreviewstrong

Ketone bodies as signaling metabolites

Newman JC, Verdin E · 2014 · Trends in Endocrinology and Metabolism

DOI: 10.1016/j.tem.2013.09.002View source ↗

“βOHB also signals via extracellular receptors and acts as an endogenous inhibitor of histone deacetylases (HDACs).”

Summary

This Trends in Endocrinology and Metabolism review reframes how the body uses ketone bodies — particularly β-hydroxybutyrate (βOHB) — beyond their traditional role as fuel. Newman and Verdin synthesize evidence that βOHB acts as a signaling molecule through at least two mechanisms. First, βOHB binds at least two cell-surface G-protein-coupled receptors (HCAR2/GPR109A and FFAR3/GPR41), modulating lipolysis, sympathetic tone, and metabolic rate. Second, βOHB directly inhibits class I histone deacetylases (HDACs), which means circulating ketones during fasting or ketogenic diets alter gene expression by changing how DNA is packaged. The review traces implications for caloric restriction, longevity, and aging-related diseases. The paper is a key citation for any claim that ketogenic diets and fasting do work beyond "running on fat instead of carbs" — they trigger gene-expression changes via epigenetic mechanisms with downstream effects on stress resistance, inflammation, and metabolic flexibility. The review is highly cited and has shaped how mechanistic ketosis research is framed.

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References cited by this entry

ExtendsThe human metabolic response to chronic ketosis without caloric restriction: preservation of submaximal exercise capability with reduced carbohydrate oxidationPhinney SD et al. · 1983
Phinney 1983 showed humans use ketones as muscle fuel; Newman/Verdin 2014 reframes ketone bodies as signaling molecules with effects beyond fuel substitution — HDAC inhibition, gene expression, and longevity-relevant pathways.
ExtendsThe effect of fasting or calorie restriction on autophagy induction: A review of the literatureBagherniya M et al. · 2018
Bagherniya's review of fasting + autophagy notes mTOR/HDAC mechanisms; Newman/Verdin specifies the mechanism — βOHB directly inhibits class-I HDACs and modulates chromatin.

Entries that reference this one

ExtendsThe therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolismVeech RL · 2004
Veech 2004 framed ketones as therapeutically useful via mitochondrial energetics; Newman/Verdin 2014 extended the framework with ketones-as-signaling-molecules (HDAC inhibition, GPCR binding) — different mechanistic angles on the same therapeutic claim.