Tissue-Specific Effects of Rosiglitazone and Exercise in the Treatment of Lipid-Induced Insulin Resistance

Abstract

Both pharmacological intervention (i.e., thiazolidinediones [TZDs]) and lifestyle modification (i.e., exercise training) are clinically effective treatments for improving whole-body insulin sensitivity. However, the mechanism(s) by which these therapies reverse lipid-induced insulin resistance in skeletal muscle is unclear. We determined the effects of 4 weeks of rosiglitazone treatment and exercise training and their combined actions (rosiglitazone treatment and exercise training) on lipid and glucose metabolism in high-fat-fed rats. High-fat feeding resulted in decreased muscle insulin sensitivity, which was associated with increased rates of palmitate uptake and the accumulation of the fatty acid metabolites ceramide and diacylglycerol. Impairments in lipid metabolism were accompanied by defects in the Akt/AS160 signaling pathway. Exercise training, but not rosiglitazone treatment, reversed these impairments, resulting in improved insulinstimulated glucose transport and increased rates of fatty acid oxidation in skeletal muscle. The improvements to glucose and lipid metabolism observed with exercise training were associated with increased AMP-activated protein kinase ␣1 activity; increased expression of Akt1, peroxisome proliferator-activated receptor ␥ coactivator 1, and GLUT4; and a decrease in AS160 expression. In contrast, rosiglitazone treatment exacerbated lipid accumulation and decreased insulin-stimulated glucose transport in skeletal muscle. However, rosiglitazone, but not exercise training, increased adipose tissue GLUT4 and acetyl CoA carboxylase expression. Both exercise training and rosiglitazone decreased liver triacylglycerol content. Although both interventions can improve whole-body insulin sensitivity, our results show that they produce divergent effects on protein expression and triglyceride storage in different tissues. Accordingly, exercise training and rosiglitazone may act as complementary therapies for the treatment of insulin resistance.

Infusion of a Lipid Emulsion Modulates AMPK and Related Proteins in Rat Liver, Muscle, and Adipose Tissues

“…Previous reports observed different effects of lipids on AMPK activation in different tissues. Recently, it has been shown that increased FA availability stimulates AMPK activity in skeletal muscle both in vitro and in vivo (10,(24)(25)(26)(27). Likewise, a diminished AMPK phosphorylation in the liver was also supported by previous works showing that TG accumulation in the liver is in association with decreased AMPK activation (27,28).…”

BNIP3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice

“…In fact, our preliminary experiments using C2C12 myotubes showed the increment in mtDNA copy number resulting from rosiglitazone exposure to be independent of BNIP3 (data not shown). Also, different PPARγ co-regulators might enable BNIP3 to act in a tissue-specific manner [35,36]. Furthermore, from our bioinformatics analysis, we could find several mitochondria-related proteins that physically interact with BNIP3 [37][38][39] and are expressed differently depending on the type of tissue.…”

“…Besides the increase in the amount of mitochondria, it was interesting to note that there was an increase in oxygen consumption and uncoupling, which suggests that BNIP3 enhances mitochondrial function in the adipocytes. The critical differences in the effect of BNIP3 in various tissues might be because of differences in the tissue-specific expression and function of PPARγ [32][33][34], PPARγ coregulators [35,36] and BNIP3-interacting proteins [37][38][39]. In fact, our preliminary experiments using C2C12 myotubes showed the increment in mtDNA copy number resulting from rosiglitazone exposure to be independent of BNIP3 (data not shown).…”

Treinamento resistido reduz inflamação em músculo esquelético e melhora a sensibilidade à insulina periférica em ratos obesos induzidos por dieta hiperlipídica

“…Diversos estudos demonstraram que a ingestão de dieta hipercalórica está associada à resistência à insulina em humanos (27) e em animais (28). Tal alteração decorre do aumento expressivo da massa adiposa que induz uma elevação da produção e liberação de proteínas que prejudicam a sinalização da insulina e a expressão de transportadores de glicose em tecidos insulino-sensíveis (2).…”

“…A expressão da proteína GLUT4, tal como a translocação para a membrana plasmática induzida por estí-mulo de insulina, é reduzida pela dieta de alto teor de gordura (28,29). Contrariamente a essas observações, no presente estudo, a dieta hiperlipídica não surtiu efeito significante na expressão de RNAm de GLUT4 nem no conteúdo proteico, porém se observou importante tendência à redução (30%) no grupo OS, quando comparado ao CS.…”