Sleeve Gastrectomy Is Associated with Improved Systemic Redox Homeostasis in T2DM Through Ghrelin–GHSR Attenuation, POMC Neuronal Modulation, and CD4 ⁺ T Cell Metabolic Reprogramming

Objective: Sleeve gastrectomy (SG) improves obesity-associated type 2 diabetes mellitus (T2DM) beyond mere weight loss. We investigated whether SG enhances systemic metabolic homeostasis by suppressing the Ghrelin–growth hormone secretagogue receptor (GHSR) axis, remodeling hypothalamic pro-opiomelanocortin (POMC) neuronal activity, and reprogramming CD4 + T cell immunometabolism. Methods: Using a diet-induced T2DM mouse model undergoing SG or Sham surgery, we integrated bulk/single-cell RNA sequencing and metabolomics to evaluate systemic neuro-immune-metabolic alterations. Functional assays validated Ghrelin’s effects on CD4 + T cell metabolism and differentiation, alongside assessments of hepatic/pancreatic function and hypothalamic neuronal activity. Results: SG globally remodeled peripheral immunity, expanding Tregs while reducing pro-inflammatory Th17 cells. scRNA-seq and metabolomic profiling revealed that CD4 + T cells shifted metabolically from glycolysis toward oxidative phosphorylation, matching increased tricarboxylic acid cycle intermediates. Functionally, Ghrelin–GHSR signaling promoted CD4 + T cell glycolysis, mitochondrial damage, and Th17 skewing; GHSR antagonism successfully reversed these detrimental effects. Systemically, SG reduced hyperglycemia and hepatic lipidosis, restored islet α/β-cell balance, activated anorexigenic POMC neurons, and suppressed AgRP neurons. Conclusion: SG alleviates T2DM through coordinated suppression of the Ghrelin–GHSR axis, bridging central appetite regulation with peripheral immunometabolic reprogramming. By shifting CD4 + T cells toward oxidative metabolism and restoring the Treg/Th17 balance, SG drives systemic metabolic recovery, providing critical molecular insights into the neuro-immune mechanisms of metabolic surgery. Antioxid. Redox Signal. 00, 000–000.