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

초록

Introduction: 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. Objective: This study investigates the function of myeloid-derived Zbtb46+ cells, a major subset of peripheral dendritic cells (DCs), in established obesity. Methods: 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. Results: 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. Conclusions: 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. (c) 2025 The Author(s). Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

키워드