Jimenez, VeronicaJambrina, ClaudiaCasana, EstefaniaSacristan, VictorMuñoz, SergioDarriba, SaraRodó, JordiMallol, CristinaGarcia, MiquelLeón, XavierMarcó, SaraRibera, AlbertElias, IvetCasellas, AlbaGrass, IgnasiElias, GemmaFerré, TuraMotas, SandraFranckhauser, SylvieMulero, FranciscaNavarro, MarcHaurigot, VirginiaRuberte, JesusBosch, Fatima2018-11-022018-11-022018-08EMBO Mol Med. 2018; 10 (8): pii: e8791.1757-4676http://hdl.handle.net/20.500.12105/6561Prevalence 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.engVoRhttp://creativecommons.org/licenses/by/4.0/AAV gene therapyFGF21insulin resistanceobesitytype 2 diabetesAtribución 4.0 Internacional29987000108e879110.15252/emmm.2017087911757-4684EMBO molecular medicineopen access