FGF21 is a novel metabolic regulator involved in the control of glucose homeostasis, insulin sensitivity, and ketogenesis. The liver has been considered the main site of production and release of FGF21 into the blood. Here, we show that, after thermogenic activation, brown adipose tissue becomes a source of systemic FGF21. This is due to a powerful cAMP-mediated pathway of regulation of FGF21 gene transcription. Norepinephrine, acting via β-adrenergic, cAMP-mediated, mechanisms and subsequent activation of protein kinase A and p38 MAPK, induces FGF21 gene transcription and also FGF21 release in brown adipocytes. ATF2 binding to the FGF21 gene promoter mediates cAMP-dependent induction of FGF21 gene transcription. FGF21 release by brown fat in vivo was assessed directly by analyzing arteriovenous differences in FGF21 concentration across interscapular brown fat, in combination with blood flow to brown adipose tissue and assessment of FGF21 half-life. This analysis demonstrates that exposure of rats to cold induced a marked release of FGF21 by brown fat in vivo, in association with a reduction in systemic FGF21 half-life. The present findings lead to the recognition of a novel pathway of regulation the FGF21 gene and an endocrine role of brown fat, as a source of FGF21 that may be especially relevant in conditions of activation of thermogenic activity.

GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.

Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.

Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis in mammals. Rodent studies indicated that BAT thermogenic activity may protect against obesity. Recent findings using novel radiodiagnosis procedures revealed unanticipated high activity of BAT in adult humans. Moreover, complex processes of cell differentiation leading to the appearance of active brown adipocytes have been recently identified. The brown adipocytes clustered in defined anatomical BAT depots of rodents arise from mesenchymal precursor cells common to the myogenic cell lineage. They are being called “classical” or “developmentally programmed” brown adipocytes. However, brown adipocytes may appear after thermogenic stimuli at anatomical sites corresponding to white adipose tissue (WAT). This process is called the “browning” of WAT. The brown adipocytes appearing in WAT derive from precursor cells different from those in classical BAT and are closer to the white adipocyte cell lineage. The brown adipocytes appearing in WAT are often called “inducible, beige, or brite.” The appearance of these inducible brown adipocytes in WAT may also involve transdifferentiation processes of white-to-brown adipose cells. There is no evidence that the ultimate thermogenic function of the beige/brite adipocytes differs from that of classical brown adipocytes, although some genetic data in rodents suggest a relevant role of the browning process in protection against obesity. Although the activation of classical BAT and the browning process share common mechanisms of induction (eg, noradrenergic-mediated induction by cold), multiple novel adrenergic-independent endocrine factors that activate BAT and the browning of WAT have been identified recently. In adult humans, BAT is mainly composed of beige/brite adipocytes, although recent data indicate the persistence of classical BAT at some anatomical sites. Understanding the biological processes controlling brown adipocyte activity and differentiation could help the design of BAT-focused strategies to increase energy expenditure and fight against obesity.