Sulforaphane Mitigates High‐Fat Diet‐Induced Obesity by Enhancing Mitochondrial Biogenesis in Skeletal Muscle via the HDAC8‐PGC1α Axis

Abstract

ScopeHistone deacetylases (HDACs) play a crucial role in the transcriptional regulation of various genes which can contribute to metabolic disorders. Although sulforaphane (SFN), a natural HDAC inhibitor, has been reported to alleviate obesity in humans and mice, the specific mechanisms and how HDACs contribute to SFN's anti‐obesity effects remain unclear.Methods and resultsOral administration of SFN in mice fed high‐fat diet increases peroxisome proliferator activating receptor γ coactivator (PGC1α)‐induced mitochondrial biogenesis in skeletal muscle. Among HDACs, SFN specifically inhibits HDAC8 activity. SFN enhances mitochondrial DNA and adenosine triphosphate (ATP) production in C2C12 myotubes, similar to the action of PCI34051, a synthetic HDAC8‐specific inhibitor. These effects are mediated by increased expression of PGC1α via upregulation of cAMP response element binding (CREB, Ser133) phosphorylation and p53 (Lys379) acetylation. These SFN‐induced effects are not observed in cells with a genetic deletion of HDAC8, suggesting the existence of a regulatory loop between HDAC8 and PGC1α in SFN's action.ConclusionSFN prevents obesity‐related metabolic dysregulation by enhancing mitochondrial biogenesis and function via targeting the HDAC8‐PGCα axis. These results suggest SFN as a beneficial anti‐obesity agent providing new insight into the role of HDAC8 in the PGC1α‐mediated mitochondrial biogenesis, which may be a novel and promising drug target for metabolic diseases.