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
Affiliations
Mohammad Abu-Odeh
Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
Yuan Zhang
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA
Shannon M. Reilly
Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
Nima Ebadat
Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
Omer Keinan
Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
Joseph M. Valentine
Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
Maziar Hafezi-Bakhtiari
Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
Hadeel Ashayer
Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
Lana Mamoun
Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
Xin Zhou
Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA
Jin Zhang
Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA; Moores Cancer Center at UC San Diego Health, La Jolla, CA 92037, USA; Department of Bioengineering, University of California San Diego, San Diego, CA 92093; Department of Chemistry and Biochemistry, University of California San Diego, San Diego, CA 92093, USA
Ruth T. Yu
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Yang Dai
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Christopher Liddle
Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead, NSW, Australia
Michael Downes
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Ronald M. Evans
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Steven A. Kliewer
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
David J. Mangelsdorf
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute
Alan R. Saltiel
Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA; Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA; Corresponding author
Summary: 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.
