Gastric resection versus clip-based gastroplasty differentially modulates neuroendocrine and metabolic responses in obese mice

Abstract Sleeve gastrectomy (SG) and non-resection, restrictive gastric procedures are increasingly used to treat severe obesity, yet the relative contributions of gastric resection versus pure restriction to metabolic remodeling remain unclear. To mechanistically dissect these components, diet-induced obese male C57BL/6J mice were randomized to either SG or a surgically clip-based sleeve gastroplasty (GP) model that narrows the gastric body without resection, or sham surgery, and longitudinally phenotyped for body weight, energy balance, glucose homeostasis, lipid metabolism, gut hormones, hypothalamic neuropeptide expression, and circulating branched-chain amino acids (BCAAs). SG and clip-based GP produced comparable weight loss over six weeks (12% and 11%, respectively). Despite similar energy expenditure, the two procedures showed distinct temporal patterns of hypophagia, with SG uniquely altering feeding microstructure. SG, but not GP, improved glucose tolerance and reduced hepatic triglyceride content in a weight-independent manner, accompanied by a selective reduction in plasma BCAAs. Hypothalamic analyses revealed reduced POMC after both interventions, whereas NPY and AgRP were selectively suppressed after SG, indicating resection-specific modulation of central orexigenic pathways. SG also elicited a more pronounced endorcine response with higher glucose-stimulated glucose-dependent insulinotropic peptide, amylin, C-peptide, insulin, glucagon, and peptide-YY. Together, these findings show that gastric resection confers additional neuroendocrine and metabolic benefits beyond those achieved by non-resection gastric restriction alone.