FGF21 Reverses Hepatic Steatosis, Increases Energy Expenditure and Improves Insulin Sensitivity in Diet-induced Obese Mice

  1. Jing Xu, Ph.D. (jingx{at},
  2. David J. Lloyd, Ph.D.1,
  3. Clarence Hale, M.S.1,
  4. Shanaka Stanislaus, B.S.1,
  5. Michelle Chen, M.S.1,
  6. Glenn Sivits, HS Diploma1,
  7. Steve N Vonderfecht, Ph.D.3,
  8. Randy Hecht, M.A.2,
  9. Luke Li, M.D.2,
  10. Richard A. Lindberg, Ph.D.1,
  11. Jin-Long Chen, Ph.D.1,
  12. Dae Young Jung, Ph.D.4,
  13. Zhiyou Zhang, M.D., Ph.D.4,
  14. Hwi Jin Ko, Ph.D.4,
  15. Jason K. Kim, Ph.D.4 and
  16. Murielle M. Véniant, Ph.D.1
  1. 1Departments of Metabolic Disorders
  2. 2Department of Protein Sciences
  3. 3Department of Pathology, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA
  4. 4Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA


    OBJECTIVES— 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 owing 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 SREBP-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.


      • Received March 19, 2008.
      • Accepted September 29, 2008.