Journal
DIABETOLOGIA
Volume 54, Issue 6, Pages 1417-1426Publisher
SPRINGER
DOI: 10.1007/s00125-011-2068-x
Keywords
Insulin resistance; Lipid metabolism; Mitochondria; Oxidative stress; Pgc-1 beta; Skeletal muscle
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Funding
- University of New South Wales
- Australian Postgraduate Awards
- Biomedical Australian Training Fellowship
- National Health and Medical Research Council of Australia
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To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1 beta [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of diet-induced insulin resistance. Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1 beta in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1 beta on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic-euglycaemic clamp. Pgc-1 beta gene expression was increased > 100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1 beta. In rats fed a HFD, increasing the levels of Pgc-1 beta partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences. Our data show that an increase in Pgc-1 beta expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.
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