Background Weight loss improves obesity-associated metabolic dysfunction, yet resolution of adipose inflammation may be incomplete and can reappear during weight regain. Whether high-dose semaglutide induces sustained immunological remodeling of adipose and hepatic tissues during weight cycling remains unclear. Methods Male C57BL/6 mice with diet-induced obesity were treated with semaglutide (60 nmol/kg, intraperitoneally, every 3 days) or vehicle for 3 weeks, followed by drug withdrawal under continued high-fat diet feeding. Body weight, body composition, and glucose homeostasis were assessed during treatment and after weight regain. Inflammatory changes in visceral and subcutaneous adipose tissue and liver were analyzed by flow cytometry, histology, immunofluorescence, and gene expression profiling. Results Semaglutide induced rapid fat mass-selective weight loss with preservation of lean mass and significantly improved fasting glucose, insulin levels, insulin sensitivity, and glucose tolerance. During treatment, visceral adipose tissue exhibited marked reductions in pro-inflammatory macrophages, crown-like structures, and inflammatory gene expression, whereas subcutaneous adipose tissue was minimally affected. Following withdrawal, mice rapidly regained weight and adiposity. Visceral adipose inflammation fully reverted, with macrophage infiltration and inflammatory gene expression comparable to chronically obese controls. Hepatic steatosis and inflammatory markers similarly returned to obese levels. Despite this tissue-level reversion, fasting glycemia and insulin levels remained partially improved. Conclusion High-dose semaglutide induces robust metabolic improvement and transient suppression of visceral adipose inflammation during active treatment; however, these inflammatory changes are not sustained after withdrawal and largely revert with weight regain. In contrast, partial improvement in fasting glycemia persisted, suggesting differential durability between systemic metabolic adaptation and local inflammatory remodeling during pharmacological weight cycling.
