LncRNA MEG3 aggravates adipocyte inflammation and insulin resistance by targeting IGF2BP2 to activate TLR4/NF-κB signaling pathway.

Abstract

Recently, emerging evidence has shown that LncRNA MEG3 is involved in adipocyte inflammation and insulin resistance progression, however, the specific mechanism of action remains unclear. In this study, we found that LncRNA MEG3 expression was increased in TNF-α stimulated 3T3-L1 mature adipocytes, and inflammatory factors IL-6 and MCP-1 secretion levels were increased, cell apoptosis and caspase3 activity was enhanced, ROS content was increased, and iNOS protein expression was increased. Moreover, TNF-α treatment attenuated glucose uptake, promoted triglyceride accumulation, inhibited GLUT4 protein expression at the plasma membrane, and reduced the phosphorylation levels of AMPK and ACC in the cells. Interestingly, we found that transfection of si-MEG3 reversed TNF-α caused inflammatory injury and insulin resistance of 3T3-L1 mature adipocytes. Next, we found that IGF2BP2 is an RNA binding protein of LncRNA MGE3 and transfection of si-IGF2BP2 reversed TNF-α caused inflammatory injury and insulin resistance in 3T3-L1 mature adipocytes, the same effects as transfection of si-MEG3. Mechanistically, LncRNA MGE3 was able to aggravate adipocyte inflammatory injury and dysregulation of insulin sensitivity by activating TLR4 pathway through upregulating the protein expression of IGF2BP2. In vivo findings showed that HFD mice with knockdown of MEG3 had reduced body weight, lower glucose concentrations and insulin levels in plasma, decreased inflammatory factors secretion, and reduced MEG3 and IGF2BP2 expression in epididymal adipose tissues and reduced fat accumulation in mice compared with HFD mice. Our results indicate that LncRNA MEG3 can aggravate chronic inflammation and insulin resistance in adipocytes by activating TLR4/NF-κB signaling pathway via targeting IGF2BP2.