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

• Published in: Molecular and cellular endocrinology 2020-02, Vol.501, p.110661, Article 110661
• Main Authors: de Mendonça, Mariana, de Sousa, Érica, da Paixão, Ailma O., Araújo dos Santos, Bruna, Roveratti Spagnol, Alexandre, Murata, Gilson M., Araújo, Hygor N., Imamura de Lima, Tanes, Passos Simões Fróes Guimarães, Dimitrius Santiago, Silveira, Leonardo R., Rodrigues, Alice C.
• Format: Article
• Language: English
• Subjects: Adipose Tissue - drug effects; Adipose Tissue - metabolism; Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diet, High-Fat - adverse effects; Disease Models, Animal; Down-Regulation - drug effects; Glucose - metabolism; Glucose Tolerance Test; Hypoglycemic Agents; Insulin - metabolism; Insulin resistance; Insulin Resistance - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Obese; MicroRNA; MicroRNAs - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Obesity; Obesity - drug therapy; Obesity - metabolism; Palmitates - pharmacology; Pioglitazone - pharmacology; PPAR alpha - metabolism; PPAR gamma - metabolism; Ppargamma; Thiazolidinediones - pharmacology; Up-Regulation - drug effects
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2019.110661

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. [Display omitted] •Pioglitazone induces mitochondrial activity in skeletal muscle.•miR-222 is decreased by pioglitazone in DIO mice in a PPARgamma-independent manner.•miR-222 is possibly involved in pioglitazone reversal of insulin resistance.•miR-222 prevents increased non-mitochondrial OCR in palmitate-treated muscle cells.