Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

Abstract

Aims/hypothesis Reductions in peroxisome proliferatoractivated receptor gamma, coactivator 1 alpha (PGC-1α) levels have been associated with the skeletal muscle insulin resistance. However, in vivo, the therapeutic potential of PGC-1α has met with failure, as supra-physiological overexpression of PGC-1α induced insulin resistance, due to fatty acid translocase (FAT)-mediated lipid accumulation. Based on physiological and metabolic considerations, we hypothesised that a modest increase in PGC-1α levels would limit FAT upregulation and improve lipid metabolism and insulin sensitivity, although these effects may differ in lean and insulin-resistant muscle. Methods Pgc-1α was transfected into lean and obese Zucker rat muscles. Two weeks later we examined mitochondrial biogenesis, intramuscular lipids (triacylglycerol, diacylglycerol, ceramide), GLUT4 and FAT levels, insulin-stimulated glucose transport and signalling protein phosphorylation (thymoma viral proto-oncogene 2 [Akt2], Akt substrate of 160 kDa [AS160]), and fatty acid oxidation in subsarcolemmal and intermyofibrillar mitochondria. Results Electrotransfection yielded physiologically relevant increases in Pgc-1α (also known as Ppargc1a) mRNA and protein (∼25%) in lean and obese muscle. This induced mitochondrial biogenesis, and increased FAT and GLUT4 levels, insulin-stimulated glucose transport, and Akt2 and AS160 phosphorylation in lean and obese animals, while bioactive intramuscular lipids were only reduced in obese muscle. Concurrently, PGC-1α increased palmitate oxidation in subsarcolemmal, but not in intermyofibrillar mitochondria, in both groups. In obese compared with lean animals, the PGC-1α-induced improvement in insulin-stimulated glucose transport was smaller, but intramuscular lipid reduction was greater. Conclusions/interpretations Increases in PGC-1α levels, similar to those that can be induced by physiological stimuli, altered intramuscular lipids and improved fatty acid oxidation, insulin signalling and insulin-stimulated glucose transport, albeit to different extents in lean and insulinresistant muscle. These positive effects are probably attributable to limiting the PGC-1α-induced increase in FAT, thereby preventing bioactive lipid accumulation as has occurred in transgenic PGC-1α animals.

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

“…Whereas the findings from these transgenic animals have been disappointing, it appears that more modest increases in the level of the PGC-1 coactivators (e.g. two-to threefold in the current study and [25,26]) avoid many of the unanticipated consequences of excessive transgene expression and result in beneficial effects with regards to insulin sensitivity. Numerous studies have demonstrated that insulin resistance is linked with increased amounts of various deleterious lipid intermediates within skeletal muscle [1,2].…”

“…An enhanced capacity for mitochondrial substrate oxidation in skeletal muscle has been linked with improved insulin action [8,9,25,26]. In the current study, rats fed an HFD displayed clear insulin resistance at the whole-body and muscle level.…”

“…Indeed recent work from Bonen et al has shown that acute overexpression of Pgc-1α in skeletal muscle of adult rats improves insulin action in both healthy and insulin-resistant muscles [25,26]. In this study our aim was to determine the effect of acute overexpression of the related coactivator Pgc-1β on markers of mitochondrial function, oxidative stress and insulin action in muscle of high-fat-fed rats.…”

Subcellular lipid droplet distribution in red and white muscles in the obese Zucker rat

“…Basal and insulin-stimulated 3-O-methylglucose uptake was measured using a submaximal concentration of insulin (150 μU/ml) in perfused rat hindlimb muscles as we have described previously [12,20].…”

EDdb: A web resource for eating disorder and its application to identify an extended adipocytokine signaling pathway related to eating disorder

“…Moreover, three genes including SOCS3 (suppressor of cytokine signaling 3), PPARGC1A (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha) and ACC2 (acetyl-CoA carboxylase beta) were included in the EXP1 dataset. Both PPARGC1A and ACC2 are involved in the regulation of fatty acid oxidation [54,55]. Though SOCS3 cannot directly influence fatty acid oxidation, it inhibits leptin activation of AMPK (5′ AMP-activated protein kinase) [56].…”