Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21

Abstract

OBJECTIVEFibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels.RESEARCH DESIGN AND METHODSThe effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks.RESULTSOleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.CONCLUSIONSThe results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.

Mice lacking have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease

“…PPARα activation increases FGF21 levels. FGF21 improves energy production by increasing the utilization of fatty acids (51) and is a potent inhibitor of hepatic steatosis (52). Our results showed that FGF21 levels were elevated in Arv1 -/ -animals.…”

Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?

“…* p <0.05, ** p <0.01 and *** p <0.001 vs vehicle-treated groups (indicated as -). Each experiment was repeated three times The increase of FGF-21 plasma concentration by exogenous glucagon regardless of endogenous insulin production is somehow intriguing, in view of the contradictory results of earlier studies showing that insulin regulates FGF-21 [12,15,17,30]. Exogenous insulin increased plasma FGF-21 and Fgf-21 mRNA expression in skeletal muscle in humans [30].…”

“…FGF-21 was detectable in four of 14 patients before and 11 of 14 patients after insulin administration. In healthy humans an approximately sevenfold increase in plasma insulin led to an approximately 10% increase in circulating FGF-21 [17]. In contrast, removal of exogenous insulin in humans with type 1 diabetes resulted in an approximately 10% increase in plasma FGF-21 [18], suggesting that insulin reduces FGF-21.…”

“…In non-diabetic humans, an approximately sevenfold increase in circulating insulin was associated with a minimal elevation of FGF-21 [17]. In contrast, circulating FGF-21 increased after insulin was removed from patients with type 1 diabetes [18].…”

Circadian Rhythm of Circulating Fibroblast Growth Factor 21 Is Related to Diurnal Changes in Fatty Acids in Humans

“…Previous studies in different ethnic groups have demonstrated an increased concentration of circulating FGF21 in obese individuals (11 ) and patients with type 2 diabetes (12 ), dyslipidemia (13 ), insulin resistance (14 ), and nonalcoholic fatty liver disease (15,16 ). The increased FGF21 concentrations in obesity are attributable to increases in free fatty acids (FFAs), which can directly stimulate FGF21 expression through the activation of PPAR␣ (17 ). Hyperinsulinemia during glucose clamping studies has been shown to induce FGF21 expression in human skeletal muscle (18 ).…”