Ketone body β-hydroxybutyrate-mediated histone β-hydroxybutyrylation upregulates lipolysis and attenuates metabolic syndrome.

Metabolic syndrome (MetS) is on the rise globally. Features of MetS include obesity, hypertension, and abnormal glucose tolerance. Exercise, keto diets, and intermittent fasting are lifestyle modifications recommended to lower MetS, all of which increase the production of the endogenous ketone body β-hydroxybutyrate. β-hydroxybutyrate has signaling and epigenetic effects, but the epigenetic mechanisms by which β-hydroxybutyrate could regulate MetS are understudied. Our previous work demonstrates that exogenous β-hydroxybutyrate supplementation lowers hypertension. The mechanism was traced to a key modification of histone-3 lysine 9 via β-hydroxybutyrylation, which remodeled the epitranscriptome to increase the accessibility of chromatin to transcriptionally upregulate key lipolytic genes, , , , and . Since lipolysis is also favorable for lowering MetS, here we hypothesized that β-hydroxybutyrate lowers MetS via upregulation of these lipolytic target genes of histone β-hydroxybutyrylation. Inbred low-capacity runner (LCR/Tol) rats were used as models of MetS and treated with or without 20% (vol/vol) 1,3-butanediol, a precursor to β-hydroxybutyrate. Rats receiving 1,3-butanediol supplementation elevated circulating β-hydroxybutyrate. In addition, histones isolated from kidneys, livers, hearts, and skeletal muscle showed increased histone-3 lysine 9 β-hydroxybutyrylation and significant transcriptional upregulation of bona fide lipolytic target genes of histone-3 lysine 9 β-hydroxybutyrylation, , , , and demonstrating sex-specific patterns. Furthermore, animals treated with 1,3-butanediol demonstrated significantly lower body weight, blood pressure, and blood glucose, with no adverse hepatic effects. Collectively, these data uncover the epigenetic effect of β-hydroxybutyrate via histone β-hydroxybutyrylation in multiple tissues as an underlying novel mechanism contributing to the observed beneficial effect of β-hydroxybutyrate to lower MetS. This is the first study to demonstrate that exogenous β-hydroxybutyrate supplementation attenuates metabolic syndrome (MetS) and identifies histone β-hydroxybutyrylation-mediated chromatin remodeling as one of the mechanisms to upregulate the transcription of the lipid catabolic genes, , , and . Our work constitutes a strong foundation for the use of 1,3-butanediol as an alternative epigenetic therapeutic for individuals who are physically unable to achieve the MetS lowering benefits of lifestyle modifications such as exercise and intermittent fasting.