FGF21 gene therapy as treatment for obesity and insulin resistance

Altres ajuts: European Foundation for the Study of Diabetes PHC-14-2015-667751. ICREA Academia Award 2014 SGR 1669. FEDER, Plan Nacional I+D+I SAF2014-54866RPrevalence 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 (21) is considered a promising therapeutic agent for T2D/obesity. Native 21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors () were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete 21. 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 21. Furthermore, 21 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 21 gene therapy to treat obesity, insulin resistance, and T2D