Mai, Knut, Andres, Janin, Biedasek, Katrin, Weicht, Jessica, Bobbert, Thomas, Sabath, Markus, Meinus, Sabine, Reinecke, Franziska, Möhlig, Matthias, Weickert, Martin O., Clemenz, Markus, Pfeiffer, Andreas F. H., Kintscher, Ulrich, Spuler, Simone and Spranger, Joachim. (2009) Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21. Diabetes, Vol.58 (No.7). pp. 1532-1538. ISSN 0012-1797

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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) –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.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology
Divisions:	Faculty of Medicine > Warwick Medical School > Clinical Sciences Research Institute (CSRI) Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Fibroblast growth factors, Lipids -- Metabolism, Fatty acids, Metabolism -- Regulation, Insulin
Journal or Publication Title:	Diabetes
Publisher:	American Diabetes Association
ISSN:	0012-1797
Date:	July 2009
Volume:	Vol.58
Number:	No.7
Page Range:	pp. 1532-1538
Identification Number:	10.2337/db08-1775
Status:	Peer Reviewed
Access rights to Published version:	Open Access
Funder:	Germany. Bundesministerium für Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG)
Grant number:	GK1208, SP716/1-1, KFO192/1
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URI:	http://wrap.warwick.ac.uk/id/eprint/3402

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