FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes

Abstract

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.

The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model

“…Some models used to study hepatic FGF21 have uncovered an important hepatic-adipose FGF21 axis that may occur in mice and possibly humans. In several studies using either extremely fasted mice (>10 hours) or mice given the β 3 -adrenergic receptor agonist CL-316,243, both of which induce or mimic increased sympathetic outflow to WAT, Hep-FGF21 exerts beneficial effects on BAT and promotes browning of WAT ( 23 , 150 , 151 ). However, humans fasted for as long as 10 days, a fasting stimulus that is sufficient to increase plasma FGF21 levels, exhibited reduced BAT activity assessed by fluorodeoxyglucose (FDG) activity ( 44 ).…”

“…Ad-KLB KO mice fed a HFD for 12 weeks did not exhibit a body weight phenotype in comparison with WT mice ( 136 , 145 ), suggesting that either (1) liver-derived FGF21 does not mediate body weight via effects on adipose tissue, or (2) autocrine adipocyte FGF21 signaling does not influence body weight. Hep-FGF21 KO mice displayed equivalent WAT browning as wild-type mice in response to CL-316,243, a β 3 -adrenergic agonist utilized to mimic increased sympathetic outflow ( 150 ). Similarly, Ad-KLB KO mice were refractory to the effects of CL-316,243 on WAT browning ( 150 ).…”

The Role of GDF15 as a Myomitokine

“…This first appears puzzling because FGF21 is known to induce WAT browning [ 77 ] and the most striking effect of FGF21 ablation in UCP1-tg mice was a complete loss of browning and WAT remodeling [ 76 ]. However, recently it was shown that the induction of browning by ß-adrenergic stimulation requires an autocrine action of FGF21 while circulating FGF21 is dispensable for WAT browning [ 78 ]. GDF15 was shown to increase sympathetic outflow to adipose tissue [ 38 ], suggesting that the increased WAT browning of UCP1-tg mice was due to a GDF15-induced adrenergic stimulation of FGF21 production in adipose tissue acting in an auto/paracrine fashion to induce the expression of thermogenic genes.…”

Exercise-Mediated Browning of White Adipose Tissue: Its Significance, Mechanism and Effectiveness

“…Both cold exposure and β3-adrenergic stimulation strongly induce FGF21 expression in scWAT through cyclic adenylate mediated activation of protein kinase A and P38 MAPK, suggesting that adipose FGF21 is a downstream effector of sympathetic activation. After specific overexpression of FGF21 in adipocytes (AD-F21 Tg), the expression of Dio2, Dusp4 and Ucp1 tended to be up-regulated, which are marker genes of WAT browning [ 40 ]. Mice with adipose tissue-specific knockout of FGF21 (A-FGF21KO) were subjected to 6-day cold exposure [ 38 ].…”

“…ERK1/2 promotes the secretion of CCL11 and mediates WAT browning. Mohammad Abu-Odeh et al [ 40 ] studied the role of KLB by using adipose-specific KLB KO (ABKO) mice. WT and ABKO mice were treated with CL-316,243 daily injections for one week.…”