FGF21 gene therapy as treatment for obesity and insulin resistance

被引：197

作者：

Jimenez, Veronica ^{[1
,2
,3
]}

Jambrina, Claudia ^{[1
,2
,3
]}

Casana, Estefania ^{[1
,2
,3
]}

Sacristan, Victor ^{[1
,2
,3
]}

Munoz, Sergio ^{[1
,2
,3
]}

Darriba, Sara ^{[1
,2
,3
]}

Rodo, Jordi ^{[1
,2
,3
]}

Mallol, Cristina ^{[1
,2
,3
]}

Garcia, Miquel ^{[1
,2
,3
]}

Leon, Xavier ^{[1
,2
,3
]}

Marco, Sara ^{[1
,2
,3
]}

Ribera, Albert ^{[1
,2
,3
]}

Elias, Ivet ^{[1
,2
,3
]}

Casellas, Alba ^{[1
,2
,3
]}

Grass, Ignasi ^{[1
,2
,3
]}

Elias, Gemma ^{[1
,2
,3
]}

Ferre, Tura ^{[1
,3
]}

Motas, Sandra ^{[1
,2
,3
]}

Franckhauser, Sylvie ^{[1
,3
]}

Mulero, Francisca ^{[3
,4
]}

Navarro, Marc ^{[1
,3
,5
]}

Haurigot, Virginia ^{[1
,2
,3
]}

Ruberte, Jesus ^{[1
,3
,5
]}

Bosch, Fatima ^{[1
,2
,3
]}

机构：

[1] Univ Autonoma Barcelona, Ctr Anim Biotechnol & Gene Therapy CBATEG, Bellaterra, Spain

[2] Univ Autonoma Barcelona, Dept Biochem & Mol Biol, Bellaterra, Spain

[3] CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain

[4] Spanish Natl Canc Res Ctr CNIO, Mol Imaging Unit, Madrid, Spain

[5] Univ Autonoma Barcelona, Sch Vet Med, Dept Anim Hlth & Anat, Bellaterra, Spain

来源：

EMBO MOLECULAR MEDICINE | 2018年 / 10卷 / 08期

关键词：

AAV gene therapy; FGF21; insulin resistance; obesity; type; 2; diabetes; GROWTH-FACTOR; 21; LEBER CONGENITAL AMAUROSIS; LONG-ACTING FGF21; ADENOASSOCIATED VIRUS; ADIPOSE-TISSUE; ENERGY-EXPENDITURE; MOUSE MODELS; REGULATES METABOLISM; ENHANCED EFFICACY; RPE65; MUTATIONS;

D O I：

10.15252/emmm.201708791

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 > 1year. 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.

引用

页数：24

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