MD2 may mediate free fatty acid‐induced inflammation and insulin resistance

Abstract

BackgroundInsulin resistance is a major metabolic abnormality of patients with obesity. Free fatty acid (FFA), whose circulating levels are often increased in obesity, causes chronic low‐grade inflammatory state that plays an important role in the development of insulin resistance. Myeloid differentiation 2 (MD2) is an assistant protein of TLR4 and plays a critical role in LPS‐induced acute inflammation. Although several reports have shown that FFA induces chronic inflammation via TLR4 signaling, it is unknown if MD2 was required in this progress.MethodLiver HL7702 cells exposed to palmitic acid (PA) were used for in vitro studies. Apoe‐/‐ mice fed with high‐fat diet and orally administrated with specific MD2 inhibitors were used. In addition, C57/BL6 mice and MD2‐knockout C57/BL6 mice were i.v. injected with PA twice a day for one week to investigate the role of MD2 in PA‐induced acute insulin resistance model.ResultsIn HL7702 cells, PA obviously induced the release of inflammatory cytokines via activation of JNK and IKKβ, and subsequent insulin resistance as evidenced by the decrease in phosphorylation of IRS1 Tyr and AKT. However, either pharmacological inhibition by two previously found small molecule inhibitors L6H21 and L6H9 or genetic silencing by MD2 siRNA significantly reversed these pathological effects induced by PA. Then, we found both oral administration with L6H21 or L6H9 in Apoe‐/‐ mice significantly attenuated the in vivo inflammation and insulin resistance. More importantly, MD2 knockout mice showed obvious tolerance in response to PA injection.ConclusionMD2 mediates PA‐induced inflammatory and subsequently insulin resistance, and MD2 may be a potential therapeutic target on obesity and insulin resistance.