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Title: FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes.

Authors: Abu-Odeh, Mohammad; Zhang, Yuan; Reilly, Shannon M; Ebadat, Nima; Keinan, Omer; Valentine, Joseph M; Hafezi-Bakhtiari, Maziar; Ashayer, Hadeel; Mamoun, Lana; Zhou, Xin; Zhang, Jin; Yu, Ruth T; Dai, Yang; Liddle, Christopher; Downes, Michael; Evans, Ronald M; Kliewer, Steven A; Mangelsdorf, David J; Saltiel, Alan R

Published In Cell Rep, (2021 Jun 29)

Abstract: The contribution of adipose-derived FGF21 to energy homeostasis is unclear. Here we show that browning of inguinal white adipose tissue (iWAT) by β-adrenergic agonists requires autocrine FGF21 signaling. Adipose-specific deletion of the FGF21 co-receptor β-Klotho renders mice unresponsive to β-adrenergic stimulation. In contrast, mice with liver-specific ablation of FGF21, which eliminates circulating FGF21, remain sensitive to β-adrenergic browning of iWAT. Concordantly, transgenic overexpression of FGF21 in adipocytes promotes browning in a β-Klotho-dependent manner without increasing circulating FGF21. Mechanistically, we show that β-adrenergic stimulation of thermogenic gene expression requires FGF21 in adipocytes to promote phosphorylation of phospholipase C-γ and mobilization of intracellular calcium. Moreover, we find that the β-adrenergic-dependent increase in circulating FGF21 occurs through an indirect mechanism in which fatty acids released by adipocyte lipolysis subsequently activate hepatic PPARα to increase FGF21 expression. These studies identify FGF21 as a cell-autonomous autocrine regulator of adipose tissue function.

PubMed ID: 34192547 Exiting the NIEHS site

MeSH Terms: 3T3-L1 Cells; Adipocytes/metabolism*; Adipose Tissue, Brown/metabolism; Adipose Tissue, White/metabolism; Adrenergic beta-Agonists; Animals; Autocrine Communication*/genetics; Fibroblast Growth Factors/blood; Fibroblast Growth Factors/genetics; Fibroblast Growth Factors/metabolism*; Gene Expression Regulation*; Lipolysis; Liver/metabolism; Mice; Organ Specificity; Protein Binding; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptors, Adrenergic, beta-3/metabolism; Receptors, Fibroblast Growth Factor/metabolism; Thermogenesis/genetics*

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