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

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 (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).

The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress

“…Yuping Song et al reported reduction of miR-592 in liver of db/db and HFD-fed mice, but no expression change in WAT. Study results indicated that miR-592 prevents obesity-induced HG, IR and hepatosteatosis [201]. Hence, its increased cellular glucose production and triggered upregulation of gluconeogenic enzymes (phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase)), due to overexpression of FOXO1.…”

Circular RNA HIPK3 contributes to hyperglycemia and insulin homeostasis by sponging miR-192-5p and upregulating transcription factor forkhead box O1

“…During fasting, however, FOXO1 promotes gluconeogenesis in the liver by inducing the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), and by inducing a transition from carbohydrate oxidation to lipid oxidation in the liver [7]. Therefore, mice overexpressing FOXO1 in the liver exhibited hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hepatosteatosis [8,9]. Furthermore, FOXO1 targets genes responsible for lipogenesis, including sterol regulatory element binding protein 1c (SREBP-1c) and fatty acid synthase (FAS) [8,10,11].…”

Obesity, Insulin Resistance, and Colorectal Cancer: Could miRNA Dysregulation Play a Role?

“…MiR-592 was reported to be downregulated in the liver of obese subjects and its overexpression in obese mice improved hepatic glucose metabolism directly targeting FOXO1. Moreover, miR-592 inhibition induced hyperglycemia, IR, and hepatic triglyceride accumulation in lean mice [71].…”