Transcriptional regulation of brown and beige adipocyte differentiation

Brown and beige adipocytes have been characterized in most detail in rodents. In humans, brown adipose tissue was thought to regress after infancy, but was shown by multiple studies published after 2007 to persist in substantial deposits into adulthood adulthood (reviewed in Bartlet and Heeren 2014, Wang and Seale 2016, Ghaben and Scherer 2019, and Cannon et al. 2020). Molecular profiles that correspond to both brown and beige rodent adipocytes have been identified in human brown-designated adipose tissue, and therefore both brown and beige adipocytes are now thought to be conserved in humans (Nedergaard et al. 2007; Virtanen et al. 2009; Cypess et al. 2009; Sharp et al. 2012; Wu et al. 2012; Nedergaard and Cannon 2013; de Jong et al. 2019; reviewed in Bartlet and Heereb 2014, Wang and Seale 2016, and Cannon et al. 2020).

The major protein marker of brown and beige adipocytes is Uncoupling protein 1 (UCP1). UCP1 resides at the inner mitochondrial membrane where it translocates protons (H+) from the intermembrane space into the mitochondrial matrix. UCP1 thus dissipates the proton-motive force to be used by ATP synthase, converting the energy released by the respiratory chain into heat (reviewed in Bartlet and Heereb 2014, Wang and Seale 2016). Brown adipose tissue is innervated by the sympathetic nervous system. Noradrenaline is secreted by sympathetic neurons when the central nervous system senses cold. Brown adipocytes possess adrenergic receptors on their surface that are activated by noradrenaline. Activated adrenergic receptors trigger a signaling cascade that induces lipolysis and activates UCP1 (reviewed in Wang and Seale 2016).

Multiple transcription factors that regulate the thermogenic molecular signature are shared between brown and beige adipocytes, such as EBF2, PRDM16, ZNF516, and PPARGC1A. Master regulators of adipogenesis, such as PPARG and CEBPB, are shared between white, brown, and beige adipocytes (reviewed in Wang and Seale 2016).

Besides its role in thermoregulation, white adipose tissue browning is implicated in cancer-associated cachexia, a complex tissue-wasting syndrome characterized by inflammation, hypermetabolism, increased energy expenditure, and anorexia (reviewed in Weber et al. 2022).

For review, please refer to Bartelt and Heeren 2014, Wang and Seale 2016, Ghaben and Scherer 2019, Cannon et al. 2020, Weber et al. 2022.