Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

Abstract

Aims/Hypothesis To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1β [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of dietinduced 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-1β in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1β 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-1β 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-1β. In rats fed a HFD, increasing the levels of Pgc-1β 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-1β 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.

Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding

“…Diacylglycerols (DGs) have been proposed to impair insulin action by activating protein kinase C isoforms and antagonising insulin signalling [5]. Elevated DGs in muscle and liver are associated with insulin resistance in humans [5,6] and animals [7,8]. Genetic manipulations in rodents that alter DG levels also support a role for this lipid intermediate as an important mediator of insulin action [9][10][11].…”

“…Ceramide is increased in tissues of insulin-resistant humans and rodents [8,13,14] and reduction of ceramide levels is associated with improved insulin sensitivity [13,15,16]. Importantly, though many studies have demonstrated a link between insulin resistance and levels of DG and ceramides, there are also several instances where alterations in insulin action and bioactive lipid content in tissues do not correlate and thus there is still substantial controversy in this area [8,17,18].…”

Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) improves skeletal muscle mitochondrial function and insulin sensitivity

“…The consequence of a Pgc-1α/Pgc-1β muscle-specific double knockout approach remains unknown. In contrast, the data provided by Wright et al [2] suggest a protective role for PGC-1β against high-fat-diet-induced insulin resistance in skeletal muscle. Similarly, the moderate and acute modulation of electroporated PGC-1α in muscle resulted in improvement of insulin sensitivity in the muscle of lean and obese Zucker rats [11].…”

“…While relative level of physical activity is the dominant regulator of Pgc-1α gene expression in skeletal muscle, transcriptional control of Pgc-1β (also known as Ppargc1b) seems less straightforward, and different effects of exercise, denervation, dietary restriction, bariatric surgery, obesity and insulin stimulation on muscle Pgc-1β mRNA levels have been described, some with conflicting results in different experimental settings (summarised in references [1][2][3][4]). The elegant study by Wright et al published in this issue of Diabetologia [2] sheds more light on the important role of PGC-1β in muscle physiology. Pgc-1β was overexpressed in electroporated tibialis cranialis and extensor digitorum longus muscles of low-fat-or high-fat-fed rats (Fig.…”

“…a more rapidly progressing insulin resistance, was reported for high-fat-fed muscle-specific Pgc-1α transgenic mice [12]. The electroporation-based approach used by Wright et al [2] to increase PGC-1β levels in individual muscles differs from the use of muscle-specific transgenic animals, which produces a stronger, chronic elevation of PGC-1β [13]. Thus, potentially confounding effects caused by the strong transgenic expression-such as the strong inhibition of Pgc-1α gene expression in the Pgc-1β muscle-specific transgenic animals [13] that could contribute to the muscle fibre-type switch observed in these mice-were not encountered by Wright et al Taking into consideration their findings and the previous work by Bonen et al [11], Wright et al propose that a moderate acute elevation of PGC-1α or PGC-1β restores insulin sensitivity, at least in glycolytic muscles in rats.…”