T‐cell immunoglobulin‐ and mucin‐domain‐containing molecule‐4 maintains adipose tissue homeostasis by orchestrating M2 macrophage polarization via nuclear factor kappa B pathway

Obesity is generally associated with low‐grade inflammation. Adipose tissue macrophages (ATMs) orchestrate metabolic inflammation. The classical (M1‐like) or alternative (M2‐like) activation of ATMs is functionally coupled with the metabolic status of fat tissues. It has been found that T‐cell immunoglobulin‐ and mucin‐domain‐containing molecule‐4 (Tim‐4) inhibits inflammation by regulating macrophages. However, the exact role of Tim‐4 in macrophage polarization and obesity remains unknown. Here, we identified Tim‐4 as a critical switch governing macrophage M1/M2 polarization and energy homeostasis. Tim‐4 deletion led to spontaneous obesity in elder mice and promoted obesity severity of db/db mice. Obesity microenvironment enhanced the expression of Tim‐4 in white adipose tissue and ATMs. In vitro, we detected an increase in M1‐like cells and decrease in M2‐like cells in both peritoneal macrophages and bone marrow‐derived macrophages from Tim‐4 knockout mice. Mechanistically, we demonstrated that Tim‐4 promoted M2‐like macrophages polarization via suppressing nuclear factor kappa B (NF‐κB) signaling pathway. In addition, we found that Tim‐4 promoted TLR4 internalization, which might contribute to regulation of NF‐κB signaling. Collectively, these results indicated that Tim‐4 maintained adipose tissue homeostasis by regulating macrophage polarization via NF‐κB pathway, which would provide a new target for obesity intervention.