Semaglutide, a novel long-acting glucagon-like peptide-1 (GLP-1) analogue, has demonstrated therapeutic benefits in renal diseases; however, its specific effects on kidney metabolism in the context of obesity remain unclear. This study aimed to investigate the renoprotective effects of semaglutide and its underlying metabolic regulatory mechanisms in obesity-associated kidney injury. Male C57BL/6J mice were assigned to control and obesity groups, with the latter receiving a high-fat diet and treatment with or without semaglutide (30 nmol/kg/day). Blood biochemical parameters were measured, and kidney damage was assessed using Periodic Acid-Schiff staining and electron microscopy. Metabolomic profiling was performed to identify obesity-related metabolic alterations in renal tissue. Semaglutide markedly improved glucose regulation, insulin sensitivity, and renal injury in obese mice. A total of 377 significantly altered metabolites (P < 0.05) were identified. Notably, semaglutide modulated metabolites linked to oxidative stress and inflammation, including nicotinamide adenine dinucleotide (NAD+) and adenosine, which have not been previously reported in obesity-related kidney injury. Pathway enrichment analysis highlighted alterations in phospholipid and lysophospholipid metabolism, purine metabolism, NAD+ metabolism, and insulin resistance-associated pathways, suggesting potential targets for therapeutic intervention.This study provides the first metabolomics-based insight into the renoprotective mechanisms of semaglutide in obese mice. The discovery of metabolites such as NAD+ and adenosine as semaglutide targets represents a novel finding in obesity-related kidney injury, supporting semaglutide as a potential treatment for obesity-associated renal disorders.
