MicroRNA miR-222 mediates pioglitazone beneficial effects on skeletal muscle of diet-induced obese mice

Author(s):Show less -

de Mendonca, Mariana ^[1] ; de Sousa, Erica ^[1] ; da Paixao, Ailma O. ^[1] ; dos Santos, Bruna Araujo ^[1] ; Spagnol, Alexandre Roveratti ^[1] ; Murata, Gilson M. ^[2] ; Araujo, Hygor N. ^{[3, 4]} ; de Lima, Tanes Imamura ^{[3, 4]} ; Passos Simoes Froes Guimaraes, Dimitrius Santiago ^{[3, 4]} ; Silveira, Leonardo R. ^{[3, 4]} ; Rodrigues, Alice C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Pharmacol, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo, SP - Brazil

^[3] Univ Estadual Campinas, UNICAMP, Inst Biol, Dept Struct & Funct Biol, Campinas, SP - Brazil

^[4] Obes & Comorbid Res Ctr, Campinas, SP - Brazil

• Document type: Journal article
• Source: Molecular and Cellular Endocrinology; v. 501, FEB 5 2020.
• Web of Science Citations: 0

Abstract

Pioglitazone belongs to the class of drugs thiazolidinediones (TZDs) and is an oral hypoglycemic drug, used in the treatment of type 2 diabetes, which improves insulin sensitivity in target tissues. Adipose tissue is the main target of pioglitazone, a PPARg and PPARa agonist; however, studies also point to skeletal muscle as a target. Non-PPAR targets of TZDs have been described, thus we aimed to study the direct effects of pioglitazone on skeletal muscle and the possible role of microRNAs as targets of this drug. Pioglitazone treatment of obese mice increased insulin-mediated glucose transport as a result of increased fatty acid oxidation and mitochondrial activity. PPARg blockage by treatment with GW9662 nullified pioglitazone's effect on systemic and muscle insulin sensitivity and citrate synthase activity of obese mice. After eight weeks of high-fat diet, miR-221-3p expression in soleus muscle was similar among the groups and miR-23b-3p and miR-222-3p were up-regulated in obese mice compared to the control group, and treatment with pioglitazone was able to reverse this condition. In vitro studies in C2C12 cells suggest that inhibition of miR-222-3p protects C2C12 cells from insulin resistance and increased non-mitochondrial respiration induced by palmitate. Together, these data demonstrate a role of pioglitazone in the downregulation of microRNAs that is not dependent on PPARg. Moreover, miR-222 may be a novel PPARg-independent mechanism through which pioglitazone improves insulin sensitivity in skeletal muscle. (AU)

• FAPESP's process: 14/22046-5 - Effect of pioglitazone on the expression of skeletal muscle microRNAs in hyperlipidic diet-induced obesity
• Grantee: Mariana de Mendonça
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 15/24789-8 - MicroRNAs on adiponectin signalling: potential therapeutical targets of insulin resistance and insulin resistance linked diseases.
• Grantee: Alice Cristina Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/05876-6 - Role of microRNAs in the development of insulin resistance
• Grantee: Alice Cristina Rodrigues
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 15/24650-0 - Role of microRNAs on control of adiponectin gene expression
• Grantee: Mariana de Mendonça
• Support Opportunities: Scholarships in Brazil - Scientific Initiation