The MyD88 inhibitor TJ-M2010-5 protects against obesity in mice by suppressing macrophage-induced metabolic inflammation

Metabolic inflammation is an important link in exacerbating obesity and insulin resistance, and the M1 polarization of macrophages is the key to the generation and maintenance of metabolic inflammation. As an inflammatory regulator, the toll-like receptor 4 (TLR4) / myeloid differentiation factor 88 (MyD88) signaling pathway plays an important role in the M1 polarization of macrophages. We previously proved that TJ-M2010-5 is a novel MyD88 inhibitor. However, the protective effect and underlying mechanisms of the MyD88 inhibitor TJ-M2010-5 against obesity induced by high fat diet (HFD) have not been reported. This study revealed that TJ-M2010-5 significantly improved the body weight, blood glucose and lipid levels of HFD mice. Histologically, TJ-M2010-5 alleviated lipid deposition in liver and adipose tissue. The proportion of M1 macrophages and the protein levels of TLR4, MyD88 and the phosphorylation ratio of nuclear factor-κB (NF-κB) in liver and epididymis adipose tissue of HFD mice were decreased after TJ-M2010-5 intervention. In vitro, TJ-M2010-5 inhibited the activation of TLR4 and MyD88 in bone marrow-derived macrophage (BMDM), significantly reduced the proportion of M1 polarization of BMDM. TJ-M2010-5 can improve obesity and its related glucose and lipid metabolism abnormalities induced by HFD through alleviating M1 polarization of macrophages and metabolic inflammation via inhibiting TLR4/MyD88 pathway.