High glucose induces hypoxanthine accumulation, linking hyperglycemia to adipocyte dysfunction

Aim: This study aimed to clarify how hyperglycemia drives metabolite-mediated remodeling in human adipocytes and to identify key metabolites that mediate high-glucose (HG)-induced remodeling of human adipocytes. Methods: Human visceral preadipocytes and mature adipocytes were exposed to HG and analyzed using metabolomics. Based on metabolomic screening, hypoxanthine was selected as the primary metabolite for functional validation. Lipid accumulation, mitochondrial respiration, and uncoupling protein 1 (UCP1) expression were assessed to determine its metabolic effects. Zebrafish fed a high-fat diet were used to evaluate in vivo effects. Pathway enrichment analyses were conducted to map metabolic and transcriptional responses. Results: HG induced widespread alterations in metabolic pathways in mature adipocytes but caused only minor alterations in precursor cells. Hypoxanthine emerged as the most consistently upregulated metabolite in HG-treated mature adipocytes. Functionally, hypoxanthine increased lipid accumulation during differentiation while suppressing UCP1 expression and mitochondrial oxidative respiration in mature adipocytes. In zebrafish, hypoxanthine aggravated diet-induced lipid deposition. Transcriptomic analysis showed glycerolipid metabolism and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were significantly enriched, suggesting that hypoxanthine may participate in adipocyte functional remodeling by regulating pathways involved in lipid metabolism and energy metabolism. Conclusion: Hypoxanthine is identified as a candidate metabolic mediator linking hyperglycemia to impaired adipocyte metabolic flexibility. By promoting lipid storage and attenuating mitochondrial and nutrient-sensing pathways, hypoxanthine contributes to glucotoxic adipocyte remodeling. These findings provide mechanistic insight into metabolite-driven adipocyte dysfunction under hyperglycemic stress and support further investigation of hypoxanthine as a potential modulator of obesity-related metabolic dysfunction.