FGF21 gene therapy as treatment for obesity and insulin resistance

EMBO Mol Med. 2018 Aug;10(8):e8791. doi: 10.15252/emmm.201708791.


Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.

Keywords: AAV gene therapy; FGF21; insulin resistance; obesity; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Body Weight
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / therapy*
  • Diet, High-Fat
  • Energy Metabolism
  • Fatty Liver / therapy
  • Fibroblast Growth Factors / genetics*
  • Fibroblast Growth Factors / metabolism
  • Fibrosis / therapy
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Hyperplasia / therapy
  • Insulin Resistance*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Muscle, Skeletal / metabolism
  • Obesity / genetics
  • Obesity / therapy*
  • Pancreatitis / therapy


  • fibroblast growth factor 21
  • Fibroblast Growth Factors