Deletion of miRNA-22 induces cardiac hypertrophy in females but attenuates obesogenic diet-mediated metabolic disorders

Obesity is a risk factor associated with cardiovascular and metabolic complications, such as hypertension, cardiac hypertrophy, dyslipidemia and type 2 diabetes. Several reports have shown the key role of microRNAs (miRNAs) in obesity-related cardiovascular and metabolic disorders. Recently, we identified that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia in males without affecting cardiac hypertrophy. In the present study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. Here, we found that loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. Wild type (WT) females treated with obesogenic diet developed cardiac hypertrophy. Interestingly, miRNA-22 knockout (KO) females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. RNA-seq analysis showed that both miRNA-22 deletion and obesogenic diet changed mRNA expression profile in females heart. Enrichment analysis revealed that genes associated with regulation of the force ofheart contraction, protein folding and fatty acid oxidation were enriched in heart of WT obese females. In addition, genes related to thyroid hormone response, heart growth and PI3K signaling were enriched in heart of miR-22 KO females. Interestingly, miR-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls, suggesting that inhibition of these genes may be preventingthe exacerbated hypertrophic response induced by obesogenic diet in miR-22 KO females. Finally, this study revealed for the first time that deletion of miRNA-22 is sufficient to induce cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic approach to treat obesity-related metabolic disorders in females.