Adipocyte GIPR and LepR Synergistically Modulate Leptin Signaling to Ameliorate Peripheral Leptin Resistance and Prevent Weight Regain in Diabetic-Obese Mice

Introduction and Objective: GIP/GLP-1 mono- or dual agonists exhibit potent weight-loss and hypoglycemic effects, but weight rebound persists after withdrawal. Adipose tissue, a key regulator of metabolic memory and weight control, secretes adipokines to maintain homeostasis. However, the direct interplay between incretins and adipokines in adipocytes remains unclear. This study aims to define adipocyte GIPR's role in leptin signaling, focusing on GIPR-LepR cross-regulation, and determine their synergistic contribution to long-term weight control and insulin sensitivity. Methods: Adipocytes and stromal vascular fractions (SVF) were isolated to assess GIPR and GLP-1R distribution. Mouse models with adipocyte-specific GIPR knockout/overexpression or leptin/LepR deficiency were treated with GIPR agonists. In vivo metabolic phenotyping, histology, and transcriptomic/proteomic analyses were performed, alongside in vitro studies using differentiated 3T3 cells or isolated mouse inguinal adipocytes. Results: Adipocytes exclusively express GIPR, not GLP-1R. GIPR agonists target adipocyte GIPR to control leptin secretion under physical or pathophysical conditions. GIPR activation enhances leptin signaling via LepR-dependent or independent manners, consequently improving peripheral leptin sensitivity in obesity or diabetes. Adipocyte-specific GIPR deletion promotes weight regain and glucose rebound. Conclusion: Our study reveals the synergistic interplay between adipocyte GIPR and LepR signaling in long-term metabolic regulation. GIPR agonism regulates leptin secretion via CREB/FOXO1 and enhances leptin signaling through JAK2-STAT3 phosphorylation, preventing weight rebound. GIPR agonists represent novel leptin sensitizers, and combined GLP-1/GIP- and leptin-based therapies hold promise for treating diabetes-associated leptin/insulin resistance and obesity. Disclosure: H. Yan: None. Funding: National Natural Science Foundation of China (82300957)