Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21

Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21 Knut Mai 1 , Janin Andres 1 , Katrin Biedasek 1 , Jessica Weicht 1 , Thomas Bobbert 1 , Markus Sabath 2 , Sabine Meinus 1 , Franziska Reinecke 1 , Matthias Möhlig 1 , Martin O. Weickert 2 , Markus Clemenz 3 , Andreas F.H. Pfeiffer 1 , 2 , Ulrich Kintscher 3 , Simone Spuler 4 and Joachim Spranger 1 , 2 1 Department 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, Berlin, Germany; 4 Muscle 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