FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number109331
JournalCell Reports
Volume35
Issue number13
DOIs
StatePublished - Jun 29 2021

Keywords

  • adipose
  • adrenergic
  • autocrine
  • beige
  • Beiging
  • Browning
  • FGF21
  • thermogenic

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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