Polystyrene nanoplastics exacerbate hepatic insulin resistance and glycolipid metabolism disorders in high‑fat diet‑induced obese mice.

Nanoplastics are emerging environmental contaminants with potential metabolic health risks, yet their chronic effects on high-fat diet (HFD)-induced obesity‑related metabolic disorders remain poorly understood. This study investigated whether long‑term oral exposure to polystyrene nanoplastics (PS‑NPs) aggravates hepatic insulin resistance and glycolipid metabolism disorders in HFD‑induced obese mice, and elucidated the underlying molecular mechanisms. Male C57BL/6 J mice were fed a HFD for 32 weeks with concurrent oral gavage of PS‑NPs (10 mg/kg, every 3 days). PS‑NPs co‑exposure significantly exacerbated body weight gain, fasting hyperglycemia, glucose intolerance, and insulin resistance compared with HFD alone. Hepatic histopathology revealed aggravated steatosis, inflammatory infiltration, and glycogen depletion in PS‑NPs‑treated obese mice. Mechanistically, PS‑NPs further suppressed hepatic protein levels of phosphorylated AKT (Ser473), insulin receptor (INSR), and glucose transporter 2 (GLUT2), while upregulating mRNA expression of gluconeogenic regulators (FOXO1, PCK1) and lipogenic genes (SREBF1, ACACA). In vitro, using HepG2 cells with high‑concentration insulin‑induced insulin resistance, PS‑NPs reduced insulin‑stimulated AKT phosphorylation, decreased INSR and GLUT2 protein expression, upregulated G6PC1 and ACACA, and downregulated SLC2A2, suggesting a cell‑autonomous sensitization to metabolic stress. Gut microbiota analysis revealed that PS‑NPs co-exposure further reduced microbial diversity and increased the Firmicutes/Bacteroidetes ratio in HFD-fed mice. Collectively, these findings indicate that HFD-induced obesity creates a metabolically vulnerable state that amplifies nanoplastic-induced hepatic insulin resistance and glycolipid dysregulation via interference with insulin signaling and transcriptional reprogramming. This positions chronic nanoplastic exposure as an underappreciated environmental driver in the obesity-diabetes nexus, highlighting the need for future risk assessment that considers host metabolic vulnerability and diet-pollutant interactions.