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Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21

Item Type:Article
Title:Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21
Creators Name:Mai, K. and Andres, J. and Biedasek, K. and Weicht, J. and Bobbert, T. and Sabath, M. and Meinus, S. and Reinecke, F. and Moehlig, M. and Weickert, M.O. and Clemenz, M. and Pfeiffer, A.F. and Kintscher, U. and Spuler, S. and Spranger, J.
Abstract: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) alpha-dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARalpha, 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 PPARgamma activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS: Oleate and linoleate increased FGF-21 expression and secretion in a PPARalpha-dependent fashion, as demonstrated by small-interfering RNA-induced PPARalpha 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.
Keywords:Cell Line, Type 2 Diabetes Mellitus, Fasting, Nonesterified Fatty Acids, Fibroblast Growth Factors, Gene Expression Regulation, Glucose Clamp Technique, Glycerol, Homeostasis, Humans, Hyperinsulinism, Hypoglycemic Agents, Lecithins, Obesity, PPAR alpha, PPAR gamma, Messenger RNA, Reference Values, Thiazolidinediones
Publisher:American Diabetes Association
Page Range:1532-1538
Date:July 2009
Official Publication:https://doi.org/10.2337/db08-1775
PubMed:View item in PubMed

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