Fibroblast Growth Factor-21 Regulates PPARγ Activity and the Antidiabetic Actions of Thiazolidinediones

Abstract

SUMMARY Fibroblast growth factor-21 (FGF21) is a circulating hepatokine that beneficially affects carbohydrate and lipid metabolism. Here we report that FGF21 is also an inducible, fed-state autocrine factor in adipose tissue that functions in a feed-forward loop to regulate the activity of peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. FGF21-knockout (KO) mice display defects in PPARγ signaling including decreased body fat and attenuation of PPARγ-dependent gene expression. Moreover, FGF21-KO mice are refractory to both the beneficial insulin-sensitizing effects and the detrimental weight gain and edema side effects of the PPARγ agonist rosiglitazone. This loss of function in FGF21-KO mice is coincident with a marked increase in the sumoylation of PPARγ, which reduces its transcriptional activity. Adding back FGF21 prevents sumoylation and restores PPARγ activity. Collectively, these results reveal FGF21 as a key mediator of the physiologic and pharmacologic actions of PPARγ.

Relationship of fibroblast growth factor 21 with baseline and new on-study microvascular disease in the Fenofibrate Intervention and Event Lowering in Diabetes study

“…Human recombinant FGF21 also increases glucose uptake in both mouse and human adipocytes [1]. FGF21 regulates peroxisome proliferator-activated receptor-γ (PPAR-γ ) and the glucose-l ow ering acti vi ty of thiazolidinediones [3,4]. Despite these beneficial effects of FGF21 in glucose metabolism in animal studies, circulating FGF21 levels are often elevated in obesity, dyslipidaemia, insulin resistance, type 2 diabetes and coronary artery disease [2,[5][6][7].…”

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

“…The endocrine actions of FGF21 are involved in the activation of BAT thermogenesis 15 and the promotion of glucose uptake by white adipocytes 16 . FGF21 also has autocrine/paracrine effects, inducing hepatic ketogenesis 9 and promoting sensitization to antidiabetic agents in WAT 17 . The cellular actions of FGF21 are mediated by FGF receptors (mainly FGFR1 and FGFR4 in adipose tissues and liver, respectively) and b-Klotho, a single-pass transmembrane protein that functions as an obligate coreceptor for FGF21 signalling 18,19 .…”

A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet

“…In addition, FGF21 is a downstream target of PPARγ and is required for the anti-diabetic effects of PPARγ agonists [13]. Moreover, hepatic FGF21 is induced by ATF4, which is activated by metformin [14].…”

“…Circulating FGF21 is liverderived and is elevated in mice fed a high-fat diet [10]. Peroxisome proliferator-activated receptor (PPAR) α, PPARγ, transcriptional factor 4 (ATF4), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) are transcriptional factors of FGF21 in the liver [11][12][13][14][15]. The role of 5-HT in the regulation of hepatic FGF21 production and circulating FGF21 in relation to insulin resistance in mice fed a high-fat diet, however, remains unclear.…”