The thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty acids, promotes brown fat activation. Using RNA-seq to analyse mouse BAT transcriptome, we find that the gene encoding GPR120 is induced by thermogenic activation. We further show that GPR120 activation induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired cold-induced browning. Omega-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF21) by brown and beige adipocytes, and increases blood FGF21 levels. The effects of GPR120 activation on BAT activation and browning are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 activates brown fat via a mechanism that involves induction of FGF21.

White adipose tissue is recognized as both a site of energy storage and an endocrine organ that produces a myriad of endocrine factors called adipokines. Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis in mammals. The amount and activity of brown adipocytes are associated with protection against obesity and associated metabolic alterations. These effects of BAT are traditionally attributed to its capacity for the oxidation of fatty acids and glucose to sustain thermogenesis. However, recent data suggest that the beneficial effects of BAT could involve a previously unrecognized endocrine role through the release of endocrine factors. Several signaling molecules with endocrine properties have been found to be released by brown fat, especially under conditions of thermogenic activation. Moreover, experimental BAT transplantation has been shown to improve glucose tolerance and insulin sensitivity mainly by influencing hepatic and cardiac function. It has been proposed that these effects are due to the release of endocrine factors by brown fat, such as insulin-like growth factor I, interleukin-6, or fibroblast growth factor-21. Further research is needed to determine whether brown fat plays an endocrine role and, if so, to comprehensively identify which endocrine factors are released by BAT. Such research may reveal novel clues for the observed association between brown adipocyte activity and a healthy metabolic profile, and it could also enlarge a current view of potential therapeutic tools for obesity and associated metabolic diseases.