Effect of pioglitazone on the expression of skeletal muscle microRNAs in hyperlipidic diet-induced obesity

Abstract

Pioglitazone is a ligand-activated receptor of peroxisome proliferator gamma (PPAR-gamma) and alpha (PPAR-alpha), nuclear receptors that control genes of lipid metabolism and glucose metabolism. This drug is an oral antidiabetic drug used in the treatment of type 2 diabetes, which improves insulin sensitivity of target tissues. Although adipose tissue appears to be the main target of agonists of PPAR- ³, clinical and pre-clinical studies indicate that the skeletal muscle is also a target. It is still unknown whether the improvement in insulin resistance in skeletal muscle by pioglitazone is a direct effect on muscle or indirect, mediated by adiponectin, a hormone secreted by adipocytes. C57BL / 6 mice fed wiht high fat diet for 16 weeks has increased adiponectin concentrations in muscle, however expression of adiponectin receptor (AdipoR1) decreased, suggesting a resistance to the action of adiponectin in this tissue. Indeed, silencing of AdipoR1 in muscle causes decreased insulin sensitivity in mice, an effect associated with mitochondrial dysfunction, since there was a decrease of ±-PCG1 a key regulator of mitochondrial function and biogenesis. The genes of the adiponectin and its receptor appear to be regulated by microRNAs (miRs); small RNAs that control gene expression by inducing the degradation of its target mRNA or blocking its translation. Mice at 10 weeks of age that overexpress adiponectin in white adipose tissue, but have no metabolic abnormalities were evaluated to profile miRNAs and miR-23b, 103-3p, -221 and -222 were shown to be decreased in the adipose tissue of these animals comparing to wild mice. So, we hypothesized that pioglitazone improves insulin sensitivity in skeletal muscle by controlling the expression of microRNAs that target adiponectin and its receptor AdipoR1.