Open AccessFGF21 gene therapy as treatment for obesity and insulin resistance
Author(s) -
Jimenez Veronica,
Jambrina Claudia,
Casana Estefania,
Sacristan Victor,
Muñoz Sergio,
Darriba Sara,
Rodó Jordi,
Mallol Cristina,
Garcia Miquel,
León Xavier,
Marcó Sara,
Ribera Albert,
Elias Ivet,
Casellas Alba,
Grass Ignasi,
Elias Gemma,
Ferré Tura,
Motas Sandra,
Franckhauser Sylvie,
Mulero Francisca,
Navarro Marc,
Haurigot Virginia,
Ruberte Jesus,
Bosch Fatima
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708791
Subject(s) - insulin resistance , obesity , fgf21 , genetic enhancement , medicine , insulin , bioinformatics , gene , diabetes mellitus , endocrinology , biology , genetics , fibroblast growth factor , receptor
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 ( FGF 21) is considered a promising therapeutic agent for T2D/obesity. Native FGF 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 ( AAV ) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF 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 FGF 21. Furthermore, FGF 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 FGF 21 gene therapy to treat obesity, insulin resistance, and T2D.