Dendritic Cell-Specific DPP4 Deficiency Attenuates Obesity-Induced Adipose Tissue Inflammation and Glucose Intolerance

Background and Objectives: Although dipeptidyl peptidase 4 (DPP4) inhibitors have been demonstrated to improve glycemic control, the diverse cellular sources and pleiotropic functions of DPP4 complicate our understanding of how it contributes to obesity-associated metabolic inflammation and cardiovascular disease.In particular, the role of immune cell-derived DPP4 in regulating adipose tissue inflammation during obesity remains poorly defined.This study aimed to elucidate the contribution of dendritic cell (DC)-derived DPP4 to obesity-associated adipose tissue inflammation and metabolic dysfunction.Methods: Mice with DC-specific Dpp4 deletion (DC-Dpp4KO mice) were obtained using the Itgax-Cre Dpp4 fl/fl system.Body weight, body composition, and glucose homeostasis were assessed under normal diet (ND) and diet-induced obesity conditions following 16 weeks of high-fat diet feeding, and epididymal white adipose tissue (eWAT), inguinal white adipose tissue (respectively), liver, spleen, and circulatory inflammatory profiles were analyzed.Results: DC-Dpp4KO mice had significantly reduced circulating DPP4 levels.Metabolic parameters were unaltered under ND conditions; however, in obese mice, loss of DC-derived DPP4 reduced visceral adiposity and improved glucose homeostasis without affecting body weight gain.Adipocyte size in eWAT was unchanged, whereas crown-like structure formation and the accumulation of adipose tissue DCs and macrophages were markedly reduced.Mechanistically, lower proportions of interleukin-6-and tumor necrosis factor-α (TNF-α)expressing adipose tissue macrophages were associated with attenuated local inflammation and substantially lower circulating and adipose TNF-α levels.Conclusions: These findings identify DC-derived DPP4 as a critical regulator of obesityinduced adipose inflammation and glucose dysfunction, linking immune-specific DPP4 activity to metabolic dysfunction and potentially increased cardiovascular disease risk.