5 research outputs found
Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21
OBJECTIVE—Fibroblast 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) –dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPAR, might modify FGF-21 levels.
RESEARCH DESIGN AND METHODS—The 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 PPAR activation was studied subsequently in a rosiglitazone
treatment trial over 8 weeks.
RESULTS—Oleate and linoleate increased FGF-21 expression
and secretion in a PPAR-dependent fashion, as demonstrated
by small-interfering RNA–induced PPAR 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.
CONCLUSIONS—The 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