Epigenetic regulation of cardiometabolic disease by HDAC-BET association

Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit dramatically enhanced thermogenic potential and, in response to high-fat feeding, attenuated obesity, insulin resistance, and hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone binding protein. At the level of the heart, we provide evidence to support a role for HDAC11 as a negative regulator of physiological hypertrophy. These findings define a novel epigenetic pathway for the regulation of energy homeostasis and cardiac growth, and suggest a potential for HDAC11-selective inhibitors for the treatment of obesity, diabetes, and associated cardiac disease.