Long noncoding RNA Gomafu upregulates Foxo1 expression to promote hepatic insulin resistance by sponging miR-139-5p

Abstract

Long non-coding RNA Gomafu is involved in diabetes-related diseases. However, its role in insulin resistance (IR) remains unclear. Our objective is to explore the role of Gomafu in hepatic IR and glucose intolerance. Gomafu expression was determined in livers of ob/ob mice and high-fat diet (HFD) mice. The binding activity of NF-κB on the Gomafu promoter was measured by chromatin immunoprecipitation and quantitative real-time PCR assays. Increased Gomafu expression was observed in the livers of obese mice. Besides, the binding of NF-κB on the Gomafu promoter was also observed in hepatocytes from ob/ob mice. Further study showed that knockdown of NF-κB p65 alleviated the increase in hepatic Gomafu expression in vivo and in vitro. Knockdown of hepatic Gomafu inhibited hepatic glucose production (HGP) and improved insulin sensitivity in obese mice, whereas, overexpression of hepatic Gomafu resulted in an increase in random and fasting blood glucose levels in lean mice. In addition, we demonstrated that Gomafu functioned as miR-139 sponge and led to the de-repression of its target gene Foxo1, which played an important role in gluconeogenesis and HGP in hepatocytes. Finally, silenced Foxo1 expression abolished the effect of Gomafu overexpression on gluconeogenesis and glucose production in hepatocytes. Taken together, our data suggested that the increase in Gomafu expression contributed to hepatic IR in obese mice.