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 FH Pfeiffer1,2,
- Ulrich Kintscher3,
- Simone Spuler4 and
- Joachim Spranger (joachim.spranger{at}charite.de)1,2
- 1) Dept. of Endocrinology, Diabetes and Nutrition, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- 2) German Institute of Nutrition, Department of Clinical Nutrition, Potsdam, Germany
- 3) Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Germany
- 4) Muscle Research Unit, Experimental and Clinical Research Center (ECRC), Charite – Universitätsmedizin Berlin, Campus Buch, Berlin, Germany
Abstract
Objective: Fibroblast growth factor 21 (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 PPARα-dependent regulator of fasting metabolism, we hypothesized that free fatty acids, 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 free fatty acids were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analysed using an euglycemic hyperinsulinemic 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 siRNA-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 here presented results 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
-
- Received December 22, 2008.
- Accepted April 14, 2009.
- Copyright © American Diabetes Association
