Siglec-E deletion alters AT macrophages phenotypes, induces an inflammatory response, and adipogenesis during diet-induced obesity

Obesity is currently a worldwide health problem, affecting more than 600 million people, and poses a threat to lifestyle and triggers metabolic complications. The infiltration of macrophages into adipose tissue (AT) plays a key role in inducing inflammation and multiple diseases during obesity. Therefore, comprehensive knowledge is required on the crosstalk between adipocytes with resident macrophages in AT to design therapeutic options for obesity and metabolic diseases. While we have demonstrated the role of Siglec-E in inflammation, the mechanism by which Siglec-E induces AT inflammation and adipogenesis remains unclear to date. Thus, this study describes how Siglec-E alters AT macrophages phenotypes, function, and adipogenesis using a high-fat diet (HFD)-induced model of obesity. We showed that during obesity, expression of Siglec-E orchestrated the infiltration of macrophages in the AT. Further, deletion of Siglec-E increased the frequency and expression of inflammatory markers and modulated macrophages towards M1 phenotypes to induce AT inflammation. We also noticed that interleukin (IL)-6 and monocyte chemoattractant protein 1 (MCP-1), inflammatory markers, increased in differentiated 3T3-L1 adipocytes after the inhibition of Siglec-E. Further, cultured 3T3-L1 adipocytes, treated with Siglec-E siRNA, show an increasing expression of peroxisome proliferator-activated receptor γ (PPARγ), NF-κB inducing kinase (NIK), NF-κB2, and decreasing expression of CCAAT-enhancer-binding protein-α (C/EBPα), and adiponectin, which in part suggests that Siglec-E is also associated with adipogenesis. Further, we observed that stromal vascular fractions (SVF) cells isolated from HFD-fed mice subjected to treatment with Siglec-E siRNAs exhibited decreased expression of the cell death-inducing DFA-like effector a (CIDEA), supporting the notion that Siglec-E might, in part, also play a role in AT browning. Taken together, our findings highlight new possibilities for the function of Siglec-E in obese conditions and instigate us to propose that Siglec-E might serve as a potential therapeutic for obesity-associated metabolic disease and AT inflammation.