Depletion of myeloid-derived Zbtb46+ cells improves glycemic control in obesity via the DPP4/GLP-1 pathway

• Dendritic cells (DCs) are key regulators of energy balance in established obesity. • Inducible DC depletion enhances metabolic health in obesity. • DCs modulate glycemia through non-inflammatory mechanisms. • Adipose tissue DCs (ATDCs) are critical regulators of DPP4 activity in obesity. • ATDCs orchestrate the DPP4/GLP-1 axis, bridging immunity and metabolism. • Targeting ATDCs presents a promising therapeutic strategy for obesity. Adipose tissue (AT) immune cells regulate metabolic functions in obesity through both inflammatory and non-inflammatory pathways. However, the specific roles and mechanisms of individual AT immune cell types in glycemic control remain poorly understood. This study investigates the function of myeloid-derived Zbtb46 + cells, a major subset of peripheral dendritic cells (DCs), in established obesity. Chimeric Zbtb46 -DTR mice were generated by transplanting bone marrow from Zbtb46 -DTR donors into wild-type recipients with distinct congenic markers. Obesity was induced with a high-fat diet (HFD; 60 % kcal from fat), and myeloid-derived Zbtb46 + cells were selectively depleted in obese mice via diphtheria toxin (DT) injection. DC-specific Dpp4 knockout (DC- Dpp4 KO) mice were generated using the Cre-loxP system and subsequently challenged with the HFD. Inducible depletion of myeloid-derived Zbtb46 + cells improves glucose homeostasis and reduces body weight in obese mice. Notably, these effects were observed even in weight-matched mice and under conditions of increased ATM accumulation, suggesting benefits independent of weight loss or AT inflammation. The improvement in glucose homeostasis was primarily mediated by elevated GLP-1 levels, which enhanced insulin secretion and decreased food intake. Increased GLP-1 was associated with decreased DPP4 activity, attributed to the depletion of ATDCs, a key contributor to circulating DPP4. Consistently, DC-specific Dpp4 deficiency confirmed that ATDC-derived DPP4 regulates GLP-1–induced insulin secretion in obesity. These findings uncover a novel, non-inflammatory role for ATDCs in glucose regulation via the DPP4/GLP-1/GLP-1R axis, positioning them as promising therapeutic targets for obesity and related metabolic diseases.