Introduction and Objective: G-protein signaling 1 (GPSM1) regulates macrophages and Treg cells in metabolic disorders, this study investigates its unexplored role in adipose tissue microvascular endothelium in obesity. Methods: Endothelial-specific GPSM1 knockout (GPSM1CKO) mice were generated. Endothelial function was evaluated via vascular permeability, microvascular density, and endothelialtomesenchymal transition (EndMT). In vitro, GPSM1 was knocked down or overexpressed in human aortic endothelial cells to analyze its regulation of EndMT.The GPSM1 antagonist AN465/42243987 was administered for in vivo validation. Results: GPSM1 was upregulated in adipose microvascular endothelium in both obese mice and humans. GPSM1CKO mice exhibited resistance to obesity, accompanied by improved insulin sensitivity, increased body energy expenditure and alleviated hepatic steatosis. These beneficial metabolic effects were attributed to the attenuation of EndMT, a finding demonstrated both in vivo and in vitro, which in turn preserved endothelial barrier integrity. Mechanistically, GPSM1 activated the cAMP/PKA/ERK axis to drive EndMT. Pharmacological GPSM1 inhibition improved vascular integrity and metabolic health in HFD-fed mice. Conclusion: Adipose endothelial GPSM1 drives obesity-associated metabolic dysfunction via the cAMP/PKA/ERK-mediated EndMT pathway, establishing GPSM1 inhibition as a promising therapeutic target for obesity. Disclosure J. Song: None. C. Zhou: None. X. Ji: None. L. Yao: None. R. Qi: None. J. Yan: None. C. Hu: None. Funding Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0549400), the Special Care Program for Obesity in Pudong Health Bureau of Shanghai (PWYq2025-01) and Academic Leaders Training Program of Pudong Health Bureau of Shanghai (PWRd2023-03)
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