title: 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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology and Institute of Biomedicine, University of Barcelona, and CIBER Fisiopatología de la Obesidad y Nutrición, 08028 Barcelona, Catalonia, Spain. hondareselayne@ub.edu
authors.forename: Elayne
authors.initials: E
authors.lastname: Hondares
authors.forename: Roser
authors.initials: R
authors.lastname: Iglesias
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Marta
authors.initials: M
authors.lastname: Giralt
authors.forename: Teresa
authors.initials: T
authors.lastname: Mampel
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
mesh_terms: D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003080:Cold Temperature; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004702:Endocrine Glands / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D051381:Rats; D017208:Rats, Wistar; D022722:Thermogenesis / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases