Down-regulation of MicroRNA-592 in obesity contributes to hyperglycemia and insulin resistanceResearch context

Abstract

Background: Many studies have demonstrated that microRNAs, a class of small and non-coding RNA molecules, play an important role in the regulation of glucose and lipid homeostasis. In the present study, we sought to investigate the function of miR-592 in the development of obesity-associated metabolic disorders, including hyperglycemia andinsulin resistance. Methods: The expression levels of miR-592 were measured in the liver of obese mice and humans by quantitative reverse transcription PCR. Loss- and gain-of function experiments were employed to explore the metabolic function of miR-592 using locked nucleic acids and adenovirus in lean and obese mice, respectively. The molecular target of miR-592 was determined by western blotting and luciferase reporter assays. Findings: We found a significant decreased expression of miR-592 in the liver of obese mice and humans. Inhibition of miR-592 led to elevated blood glucose levels, enhanced gluconeogenesis and reduced insulin sensitivity in lean mice. In contrast, adenovirus-mediated overexpression of hepatic miR-592 improved metabolic disorders in obese mice. Mechanistically, we found that the transcription factor forkhead box O1 (FOXO1) is a direct target gene of miR-592 to mediate its metabolic functions. miR-592 was able to inhibit the mRNA and protein expression of FOXO1 by binding to its 3′-untranslated region. Interpretations: Our findings demonstrate that obesity-associated down-regulation of miR-592 plays an important role in the progression of metabolic diseases. Restoration of hepatic miR-592 could improve glucose and lipid metabolism in obese mice. Fund: This work is supported by the National Key Research and Development Program of China (No. 2016YFC1304805 to Dr. Chen), Natural Science Foundation of China (No. 81771574 to Dr. Wu), Shanghai Science Foundation (No. 18ZR1437800 to Dr. Li), Science and Technology Commission of Shanghai Municipality (Nos.18dz2304400 and 15,411,970,700 to Dr. Yang). Keywords: Obesity, Gluconeogenesis, Insulin resistance, Liver steatosis, MicroRNAs, FOXO1