Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21
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
WRAP_Weickert_-mai_weickert_diabetes2009.pdf - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Official URL: http://dx.doi.org/10.2337/db08-1775
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|
|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|
|Official Date:||July 2009|
|Page Range:||pp. 1532-1538|
|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|
1. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R,
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