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

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-Dpp4KO) 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.