Metabolomics Provides Insights into Renoprotective Effects of Semaglutide in Obese Mice

PURPOSE: Semaglutide, a new long-acting glucagon-like peptide-1 analogue, has shown benefits for renal diseases, but its direct role on kidney metabolism under obesity remains unclear. The study aims to elucidate the protective effect and metabolic modulation mechanism of semaglutide on obesity-related kidney injury. METHODS: Male C57BL/6J mice were divided into control and obesity groups. Mice in the obesity group had a high-fat diet and were treated with or without semaglutide (30nmol/kg/day). The study assayed blood biochemistry and then evaluated renal pathological injury through Periodic Acid-Schiff staining and electron microscopy. Metabolomics was utilized to analyze obesity-related metabolites in kidney samples. RESULTS: Semaglutide significantly improved glucose homeostasis, insulin resistance, and kidney injury in obese mice. We successfully identified 377 altered metabolites (P<0.05). It was suggested that semaglutide directly improved oxidative stress and inflammation-related metabolites such as nicotinamide adenine dinucleotide (NAD(+)) and adenosine in the kidney of obese mice, which have not been documented in obesity-related kidney injury. Relevant enriched pathways were included phospholipids and lysophospholipids metabolism, purine metabolism, NAD(+) metabolism, and insulin resistance-related metabolism. They could serve as potential targets for intervention of obesity-related kidney injury. CONCLUSION: Our study revealed the metabolomics-based renoprotective mechanism of semaglutide in obese mice for the first time. The innovation lied in the identified metabolites such as NAD(+) and adenosine targeted by semaglutide, which have not been documented in obesity-related kidney injury. Semaglutide may be a promising therapy for obesity-related kidney diseases.