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Am J Physiol Endocrinol Metab. 2014 Nov 1;307(9):E764-72. doi: 10.1152/ajpendo.00001.2014. Epub 2014 Aug 26.

High-fat diet-induced impairment of skeletal muscle insulin sensitivity is not prevented by SIRT1 overexpression.

Author information

1
Department of Orthopaedic Surgery, University of California San Diego, La Jolla, California; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California;
2
School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, United Kingdom;
3
Department of Anesthesiology, University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California;
4
Department of Pharmacology, University of California San Diego, La Jolla, California;
5
Health and Exercise Sciences Research Group, School of Sport, University of Stirling, Stirling, United Kingdom; and.
6
Department of Human Physiology, University of Oregon, Eugene, Oregon.
7
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.

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.

KEYWORDS:

SIRT1; high-fat diet; insulin resistance; skeletal muscle

PMID:
25159328
PMCID:
PMC4216952
DOI:
10.1152/ajpendo.00001.2014
[Indexed for MEDLINE]
Free PMC Article

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