Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21
- Knut Mai1,
- Janin Andres1,
- Katrin Biedasek1,
- Jessica Weicht1,
- Thomas Bobbert1,
- Markus Sabath2,
- Sabine Meinus1,
- Franziska Reinecke1,
- Matthias Möhlig1,
- Martin O. Weickert2,
- Markus Clemenz3,
- Andreas F.H. Pfeiffer1,2,
- Ulrich Kintscher3,
- Simone Spuler4 and
- Joachim Spranger1,2
- 1Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany;
- 2German Institute of Nutrition, Department of Clinical Nutrition, Potsdam, Germany;
- 3Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany;
- 4Muscle Research Unit, Experimental and Clinical Research Center, Charite-Universitätsmedizin Berlin, Campus Buch, Berlin, Germany.
- Corresponding author: Joachim Spranger, joachim.spranger{at}charite.de.
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) 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 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 PPARγ activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks.
RESULTS Oleate 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.
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.
Footnotes
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Clinical trial reg. no. NCT00473603, clinicaltrials.gov.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received December 22, 2008.
- Accepted April 14, 2009.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
- © 2009 by the American Diabetes Association.
