title: AAV-mediatedSirt1overexpression in skeletal muscle activates oxidative capacity but does not prevent insulin resistance.
abstract: Type 2 diabetes is characterized by triglyceride accumulation and reduced lipid oxidation capacity in skeletal muscle. SIRT1 is a key protein in the regulation of lipid oxidation and its expression is reduced in the skeletal muscle of insulin resistant mice. In this tissue,Sirt1up-regulates the expression of genes involved in oxidative metabolism and improves mitochondrial function mainly through PPARGC1 deacetylation. Here we examined whetherSirt1overexpression mediated by adeno-associated viral vectors of serotype 1 (AAV1) specifically in skeletal muscle can counteract the development of insulin resistance induced by a high fat diet in mice. AAV1-Sirt1-treated mice showed up-regulated expression of key genes related to β-oxidation together with increased levels of phosphorylated AMP protein kinase. Moreover, SIRT1 overexpression in skeletal muscle also increased basal phosphorylated levels of AKT. However, AAV1-Sirt1treatment was not enough to prevent high fat diet-induced obesity and insulin resistance. AlthoughSirt1gene transfer to skeletal muscle induced changes at the muscular level related with lipid and glucose homeostasis, our data indicate that overexpression of SIRT1 in skeletal muscle is not enough to improve whole-body insulin resistance and that suggests that SIRT1 has to be increased in other metabolic tissues to prevent insulin resistance.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Vilà
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Roca
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Ivet
authors.initials: I
authors.lastname: Elias
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Casellas
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lage
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Franckhauser
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch