FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes

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