Thermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue

Abstract

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 ␤-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.Fibroblast growth factor 21 (FGF21) is a metabolic regulator involved in the control of glucose homeostasis, insulin sensitivity, and ketogenesis (1-4). Treatment with FGF21 corrects metabolic disturbances such as hyperglycemia and insulin resistance in rodent models of obesity and diabetes (1, 5-7). It also has been reported that FGF21 exerts autocrine and paracrine actions on livers that promote ketogenesis (2-4). Two recent studies in FGF21 gene-ablated mice have demonstrated that FGF21 is required for the physiological response of mice to fasting and to ketogenic diets (8, 9), although a third study did not confirm these observations (10). Moreover, FGF21 favors glucose utilization in white adipose tissue (WAT), 2 and there are conflicting data on to whether FGF21 activates or does not activate lipolysis in white fat (3, 10, 11). Recently, FGF21 has been reported to promote thermogenic activity in neonatal brown adipose tissue (BAT) and in isolated brown adipocytes (12); there are indications that FGF21 may also promote BAT thermogenic activation in adult mice (1, 6, 7). The liver is considered the main site of production and release of FGF21 into the blood. Expression of the FGF21 gene in the liver is under the control of PPAR␣, and fatty acid availability, acting via PPAR␣, seems to be the main determinant of hepatic FGF21 gene expression and release (2, 3,12,13). Extra-hepatic tissues, including white and brown adipose tissues and skeletal muscle, also express the FGF21 gene (14), and PPAR␥ activation has been reported to induce FGF21 gene expression in white adipocytes (14,15). On the basis of cell culture studies, muscle cells have been proposed to be capabl...

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

“…The basal rate of FGF21 secretion in media under control conditions was B0.05 ng ml À 1 24 h À 1 . This basal CM FGF21 secretion rate was lower than that of mouse primary hepatocytes (B0.17 ng ml À 1 24 h À 1 ) 22 and brown adipocytes (B0.3 ng ml À 1 24 h À 1 ) 14 . After treatment with phenylephrine, the rate of FGF21 protein secretion by NCMs in culture significantly increased reaching B0.15 ng ml À 1 24 h À 1 , closer to secretion rates in classical FGF21-producing cells.…”

Brown and beige fat: development, function and therapeutic potential

“…Fibroblast growth factor 21 (FGF21) is a circulating hormone that regulates systemic energy levels and has npg become a focus of clinical trials for obesity, diabetes and cardiovascular disease. In BAT, Fgf21 expression is increased by cold exposure and has an important role in thermogenesis 131,132 . Interestingly, there is a marked burst of Fgf21 production from the neonate liver in response to suckling-this effect is probably crucial for activating BAT thermogenesis at a time when animals are especially vulnerable to hypothermia 133 .…”

Non-sympathetic control of brown adipose tissue

“…48,49 It is also notable that BAT itself releases FGF21 in response to thermogenic stimuli, suggesting a potential autocrine action of BAT-derived FGF21. 50 Interestingly, it has recently been found that, in humans, FGF21 is preferentially expressed in BAT versus WAT, thereby reinforcing the possibility of an autocrine role of BAT-derived FGF21 in addition to the endocrine role of hepatic FGF21. 51 In human obese patients and in rodent models of obesity, it has been observed that FGF21 levels in blood are abnormally increased, 52,53 leading to the suggestion that obesity may constitute an FGF21-resistant state.…”