Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1beta involves reductions in long-chain acyl-CoA levels and oxidative stress
AIMS/HYPOTHESIS: To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1beta [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of diet-induced insulin resistance. METHODS: Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1beta in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1beta 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. RESULTS: Pgc-1beta 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-1beta. In rats fed a HFD, increasing the levels of Pgc-1beta partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences. CONCLUSIONS: Our data show that an increase in Pgc-1beta 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.
|Authors||Wright, L. E.; Brandon, A. E.; Hoy, A. J.; Forsberg, G. B.; Lelliott, C. J.; Reznick, J.; Lofgren, L.; Oscarsson, J.; Stromstedt, M.; Cooney, G. J.; Turner, N.:|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10593|