TY - JOUR
T1 - FGF21 gene therapy as treatment for obesity and insulin resistance
AU - Jimenez, Veronica
AU - Jambrina, Claudia
AU - Casana, Estefania
AU - Sacristan, Victor
AU - Muñoz, Sergio
AU - Darriba, Sara
AU - Rodó, Jordi
AU - Mallol, Cristina
AU - Garcia, Miquel
AU - León, Xavier
AU - Marcó, Sara
AU - Ribera, Albert
AU - Elias, Ivet
AU - Casellas, Alba
AU - Grass, Ignasi
AU - Elias, Gemma
AU - Ferré, Tura
AU - Motas, Sandra
AU - Franckhauser, Sylvie
AU - Mulero, Francisca
AU - Navarro, Marc
AU - Haurigot, Virginia
AU - Ruberte, Jesus
AU - Bosch, Fatima
N1 - Funding Information:
This work was supported by grants from Ministerio de Economía y Competi-tividad (MINECO) and FEDER, Plan Nacional I+D+I (SAF2014-54866R), and Generalitat de Catalunya (2014 SGR 1669 and ICREA Academia Award to F.B.), Spain, from the European Commission (MYOCURE, PHC-14-2015-667751) and the European Foundation for the Study of Diabetes (EFSD/MSD European Research Programme on Novel Therapies for Type 2 Diabetes, 2013). V.J. was recipient of a post-doctoral research fellowship from EFSD/ Lilly. E.C., V.S., and C.M. received a predoctoral fellowship from Ministerio de Educación, Cultura y Deporte, and J.R. from Ministerio de Economía y Competitividad, Spain. The authors thank Marta Moya and Maria Molas for technical assistance.
Funding Information:
This work was supported by grants from Ministerio de Econom?a y Competitividad (MINECO) and FEDER, Plan Nacional I+D+I (SAF2014-54866R), and Generalitat de Catalunya (2014 SGR 1669 and ICREA Academia Award to F.B.), Spain, from the European Commission (MYOCURE, PHC-14-2015-667751) and the European Foundation for the Study of Diabetes (EFSD/MSD European Research Programme on Novel Therapies for Type 2 Diabetes, 2013). V.J. was recipient of a post-doctoral research fellowship from EFSD/Lilly. E.C., V.S., and C.M. received a predoctoral fellowship from Ministerio de Educaci?n, Cultura y Deporte, and J.R. from Ministerio de Econom?a y Competitividad, Spain. The authors thank Marta Moya and Maria Molas for technical assistance.
Publisher Copyright:
© 2018 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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.
KW - AAV gene therapy
KW - FGF21
KW - insulin resistance
KW - obesity
KW - type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85050455257&partnerID=8YFLogxK
U2 - 10.15252/emmm.201708791
DO - 10.15252/emmm.201708791
M3 - Article
C2 - 29987000
SN - 1757-4676
VL - 10
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 8
M1 - e8791
ER -
