Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge

Histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. How brown fat keeps us from the cold Brown adipose tissue (BAT), or brown fat, protects against hypothermia by generating heat. Mitchell Lazar and colleagues discovered a critical and novel role of the epigenetic modulator HDAC3 in controlling the ability of BAT to respond to acute thermogenic challenges. They report that histone deacetylase 3 (HDAC3) acts in BAT as a transcriptional coactivator to ensure basal transcription of BAT-specific genes, independent of adrenergic stimulation. HDAC3 primes UCP1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in BAT that can be rapidly engaged for thermogenic respiration and heat production on demand. This improves our understanding of the physiological basis for mammalian response to extreme cold exposure. Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease 1 . However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor 2 , it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1 , Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.