title: High-fat diet-induced impairment of skeletal muscle insulin sensitivity is not prevented by SIRT1 overexpression.
abstract: Skeletal muscle sirtuin 1 (SIRT1) expression is reduced under insulin-resistant conditions, such as those resulting from high-fat diet (HFD) feeding and obesity. Herein, we investigated whether constitutive activation of SIRT1 in skeletal muscle prevents HFD-induced muscle insulin resistance. To address this, mice with muscle-specific overexpression of SIRT1 (mOX) and wild-type (WT) littermates were fed a control diet (10% calories from fat) or HFD (60% of calories from fat) for 12 wk. Magnetic resonance imaging and indirect calorimetry were used to measure body composition and energy expenditure, respectively. Whole body glucose metabolism was assessed by oral glucose tolerance test, and insulin-stimulated glucose uptake was measured at a physiological insulin concentration in isolated soleus and extensor digitorum longus muscles. Although SIRT1 was significantly overexpressed in muscle of mOX vs. WT mice, body weight and percent body fat were similarly increased by HFD for both genotypes, and energy expenditure was unaffected by diet or genotype. Importantly, impairments in glucose tolerance and insulin-mediated activation of glucose uptake in skeletal muscle that occurred with HFD feeding were not prevented in mOX mice. In contrast, mOX mice showed enhanced postischemic cardiac functional recovery compared with WT mice, confirming the physiological functionality of the SIRT1 transgene in this mouse model. Together, these results demonstrate that activation of SIRT1 in skeletal muscle alone does not prevent HFD-induced glucose intolerance, weight gain, or insulin resistance.
authors.affiliation: Department of Orthopaedic Surgery, University of California San Diego, La Jolla, California; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California;
authors.forename: Amanda T
authors.initials: AT
authors.lastname: White
authors.affiliation: School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, United Kingdom;
authors.forename: Andrew
authors.initials: A
authors.lastname: Philp
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California;
authors.forename: Heidi N
authors.initials: HN
authors.lastname: Fridolfsson
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California;
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schilling
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California;
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.affiliation: Health and Exercise Sciences Research Group, School of Sport, University of Stirling, Stirling, United Kingdom; and.
authors.forename: D Lee
authors.initials: DL
authors.lastname: Hamilton
authors.affiliation: Department of Human Physiology, University of Oregon, Eugene, Oregon.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: McCurdy
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California;
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.affiliation: Department of Orthopaedic Surgery, University of California San Diego, La Jolla, California; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California; sschenk@ucsd.edu.
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
mesh_terms: D050154:Adiposity; D000818:Animals; D001823:Body Composition; D059305:Diet, High-Fat / Q000009:adverse effects*; D004734:Energy Metabolism; D018149:Glucose Intolerance / Q000209:etiology*; D006321:Heart / Q000503:physiopathology; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D010101:Oxygen Consumption; D011897:Random Allocation; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D015430:Weight Gain
chemical_list: C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: SIRT1; high-fat diet; insulin resistance; skeletal muscle