Thermogenic Gene Expression in WT vs FGF21KO Adipocytes

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, b-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. 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. These studies define FGF21 as a cell-autonomous autocrine regulator of adipose tissue function.