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oai:repisalud.isciii.es:20.500.12105/65612024-11-29T21:02:37Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Jimenez, Veronica author Jambrina, Claudia author Casana, Estefania author Sacristan, Victor author Muñoz, Sergio author Darriba, Sara author Rodó, Jordi author Mallol, Cristina author Garcia, Miquel author León, Xavier author Marcó, Sara author Ribera, Albert author Elias, Ivet author Casellas, Alba author Grass, Ignasi author Elias, Gemma author Ferré, Tura author Motas, Sandra author Franckhauser, Sylvie author Mulero, Francisca author Navarro, Marc author Haurigot, Virginia author Ruberte, Jesus author Bosch, Fatima author 2018-08 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. EMBO Mol Med. 2018; 10 (8): pii: e8791. 10.15252/emmm.201708791 1757-4684 1757-4676 EMBO molecular medicine 29987000 http://hdl.handle.net/20.500.12105/6561 AAV gene therapy FGF21 insulin resistance obesity type 2 diabetes FGF21 gene therapy as treatment for obesity and insulin resistance