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

• Grant number: 14/22046-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2014
• End date: October 31, 2015
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Alice Cristina Rodrigues
• Grantee: Mariana de Mendonça
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 11/05876-6 - Role of microRNAs in the development of insulin resistance, AP.JP

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.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE MENDONCA, MARIANA; DE SOUSA, ERICA; DA PAIXAO, AILMA O.; DOS SANTOS, BRUNA ARAUJO; SPAGNOL, ALEXANDRE ROVERATTI; MURATA, GILSON M.; ARAUJO, HYGOR N.; DE LIMA, TANES IMAMURA; PASSOS SIMOES FROES GUIMARAES, DIMITRIUS SANTIAGO; SILVEIRA, LEONARDO R.; et al. MicroRNA miR-222 mediates pioglitazone beneficial effects on skeletal muscle of diet-induced obese mice. Molecular and Cellular Endocrinology, v. 501, FEB 5 2020. (14/22046-5, 15/24789-8, 11/05876-6, 15/24650-0)