Transcriptional and epigenetic control of brown and beige adipose cell fate and function

Key Points Brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function is coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. Histone modification, DNA methylation and chromatin conformational changes have crucial roles in the determination and maintenance of brown and beige adipocyte fate. Currently, more than 50 transcriptional regulators are known to control brown or beige adipocyte differentiation. A large proportion of the regulators, if not all of them, function through master regulators such as peroxisome proliferator-activated receptor-γ (PPARγ) and their partners CCAAT/enhancer-binding protein-ß (C/EBPβ), PR domain zinc-finger protein 16 (PRDM16) and PPARγ co-activator-1α (PGC1α). Various external stimuli, such as chronic cold exposure and synthetic PPARγ ligands, promote beige adipocyte biogenesis in adipocyte precursors. These cues are sensed by cell surface receptors (such as the β-adrenergic receptor) and nuclear receptors (such as PPARγ), leading to dynamic changes in chromatin structures, as well as changes in expression and activity of the key transcriptional regulators. Embryonic, brown adipocytes, together with beige, brown-like adipocytes induced in white fat depots in response to various stimuli, constitute specialized heat-producing fat cells that contribute to organismal energy expenditure. Important insights have now been gained into the transcriptional and epigenetic regulation of biogenesis and thermogenesis of these cells, opening up new possibilities for the treatment of metabolic disorders. White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated di