Abstract
SUMMARYThe 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.
Highlights
FGF21 is a member of the fibroblast growth factor (FGF) superfamily of growth factors (Beenken and Mohammadi, 2009)
FGF21 is produced in response to b-3 adrenergic activation in multiple tissues several studies suggest that circulating FGF21 is largely produced by the liver (Ameka et al, 2019; Liang et al, 2014; Markan et al, 2014), its mRNA is expressed in other tissues, where it might act as an autocrine or paracrine factor
One such tissue is adipose tissue; FGF21 expression is induced in response to b-adrenergic agonists in brown adipose tissue (BAT) and WAT in mice (Chartoumpekis et al, 2011; Peng et al, 2015)
Summary
FGF21 is a member of the fibroblast growth factor (FGF) superfamily of growth factors (Beenken and Mohammadi, 2009). FGF21 is synthesized by several organs, where it is induced by various states of stress, including cold and fasting (BonDurant and Potthoff, 2018; Fisher and Maratos-Flier, 2016; Kharitonenkov and DiMarchi, 2017; Kliewer and Mangelsdorf, 2019). FGF21 exerts its effects by binding to a heteromeric receptor comprised of FGF receptor 1c (FGFR1c) and the obligate co-receptor b-Klotho (BonDurant and Potthoff, 2018; Fisher and Maratos-Flier, 2016; Kharitonenkov and DiMarchi, 2017; Kliewer and Mangelsdorf, 2019). Exogenous administration of FGF21 to obese mice induces weight loss, corrects hyperlipidemia, reduces inflammation, lowers blood sugar and insulin resistance, and improves fatty liver
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