Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in
Diet-Induced Obese Mice
Jing Xu 1 ,
David J. Lloyd 1 ,
Clarence Hale 1 ,
Shanaka Stanislaus 1 ,
Michelle Chen 1 ,
Glenn Sivits 1 ,
Steven Vonderfecht 2 ,
Randy Hecht 3 ,
Yue-Sheng Li 3 ,
Richard A. Lindberg 1 ,
Jin-Long Chen 1 ,
Dae Young Jung 4 ,
Zhiyou Zhang 4 ,
Hwi-Jin Ko 4 ,
Jason K. Kim 4 and
Murielle M. Véniant 1
1 Department of Metabolic Disorders, Amgen, Thousand Oaks, California
2 Department of Pathology, Amgen, Thousand Oaks, California
3 Department of Protein Sciences, Amgen, Thousand Oaks, California
4 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
Corresponding author: Jing Xu, jingx{at}amgen.com
Abstract
OBJECTIVE— Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims
of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose
and lipid-lowering effects in a high-fat diet–induced obesity (DIO) model.
RESEARCH DESIGN AND METHODS— DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight,
glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity
were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques.
RESULTS— FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure
and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis.
The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element
binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also
dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body
weight and adiposity.
CONCLUSIONS— FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic
steatosis, obesity, and type 2 diabetes.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 7 October 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
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Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

10.2337/db08-0392