Semaglutide Modulates Visceral Adipose Tissue Lipid Metabolism in Type 2 Diabetic Mice: A Lipidomics Study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major public health challenge. This study aimed to explore the molecular mechanisms underlying the effects of semaglutide on lipid metabolism in visceral white adipose tissue in a mouse model of T2DM. METHODS: Male C57BL/6J mice were given a normal diet, a high-fat diet with streptozotocin, or a high-fat diet with semaglutide. Blood samples, liver tissue, and adipose tissue were collected for analysis. Serum adipokines, inflammatory cytokines, liver function, and lipid profiles were assessed. White adipose tissue and liver sections were processed for hematoxylin and eosin (H&E) staining or immunohistochemistry (IHC) staining for the macrophage marker F4/80. High-throughput targeted lipidomic analysis of epididymal white adipose tissue from these animals was performed using liquid chromatography-tandem mass spectrometry to characterize changes in lipid composition and function. Furthermore, the expression of genes related to adipokines, inflammation, and lipid metabolism in epididymal adipose tissue was determined by reverse transcription-quantitative PCR (RT-qPCR). RESULTS: Semaglutide significantly improved systemic metabolism in mice with T2DM, as demonstrated by reductions in body weight, blood glucose, serum lipid levels, and insulin resistance indices homeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance index (Adipo-IR). Serum Leptin, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) levels were downregulated, while Adiponectin levels were elevated. Histological analysis revealed that semaglutide effectively reduced adipocyte size, suppressed macrophage infiltration in adipose tissue, and decreased liver lipid accumulation. Targeted lipidomic profiling identified 24 lipid subclasses, of which 50 lipid molecules were significantly changed after semaglutide treatment. Enrichment analysis identified 15 metabolic pathways, with glycerophospholipid metabolism being the most prominently affected. RT-qPCR results confirmed that semaglutide altered the expression of key genes involved in glycerolipid, glycerophospholipid, fatty acid, and cholesterol metabolism. CONCLUSIONS: These results shed light on the comprehensive remodeling of semaglutide in improving lipid metabolism in epididymal white adipose tissue mice with T2DM.