Thermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue*

By E. Hondares, R. Iglesias, A. Giralt, F. Gonzalez, M. Giralt, T. Mampel, F. Villarroya. Journal of Biological Chemistry, 2011

596 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/851d0e79e20bdef2c8a11f8e00d57812ac737861

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1. L. Sidossis
2. Jun Wu
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Citations in the corpus

• Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. (2013, background): “There is also good evidence that FGF21 is involved in the thermogenic functions of brown adipocytes (Hondares et al., 2011; Potthoff et al., 2012).”
• Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist (2015, background): “In addition to improving energy balance, rodent models have shown that chronic stimulation of BAT leads to improved glucose tolerance and the release of adipokines that beneficially regulate metabolism (Bartelt et al., 2011; Hondares et al., 2011).”
• Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease (2020, background): “In later studies, a thermogenic role for adipose-derived Fgf21 has been described, in which the browning of WAT was shown to require adipocyteFgf21 (141, 166).”
• Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. (2014, background): “, 2012), is activated with ST, we explored whether FGF21, a brown adipokine in rodents (Chartoumpekis et al., 2011; Hondares et al., 2011) and humans (Lee et al.”
• Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans (2014, background): “Adrenergic stimulation and FT3 are upstream regulators of FGF21 production.”
• Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. (2013, unknown): “Since BAT and liver are major sources of FGF21 (21, 22), we measured FGF21 protein levels in these tissues.”
• FGF/FGFR signaling in health and disease (2020, background): “FGF21 in BAT is induced by cold exposure.(561) FGF21 stimulates glucose uptake in adipocytes in an insulinindependent manner through induction of GLUT1 expression,(562) and inhibits lipolysis of adipocytes.”
• FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. (2012, background): “In addition, two recent reports demonstrated that FGF21mRNA expression is induced in classical BATupon cold stimulus (Chartoumpekis et al. 2011; Hondares et al. 2011).”