IMI targets abnormal lipid metabolism by inhibiting intestinal TAS2Rs.

Imidacloprid (IMI), a widely used neonicotinoid insecticide, has been increasingly linked to metabolic disorders from environmental exposure. In this study, adult rats were chronically exposed to low-dose IMI at 0.06 mg/kg body weight per day for 19 weeks under three dietary regimens: normal-fat, high-fat, and free-choice diets. Prolonged IMI treatment significantly increased body weight, induced dyslipidemia characterized by elevated serum total cholesterol and triglycerides, reduced high-density lipoprotein cholesterol and triggered systemic inflammation. Notably, under normal-fat diet, IMI disrupted lipid metabolism via crosstalk between intestinal TAS2Rs (TAS2Rs) and fat receptor 41 (GPR41). Under high-fat and free-choice diets, the effects are mainly associated with cluster of differentiation 36 (CD36) mediated PKC-AMPK-Acetyl CoA carboxylase 1 (ACC1) signaling pathway. However, the relationship between this pathway and the decreased expression of TAS2Rs remains unclear, indicating that a high-fat dietary state may interfere with the flavor perception toxicity of IMI. The result of 16S rRNA sequencing showed IMI reduced gut microbial diversity, increased pathogenic Clostridium, and decreased beneficial Bacteroides. Spearman correlation analysis indicated that TAS2R119 expression positively correlated with Bacteroides abundance and negatively with norank_o__Clostridia_UCG-014, suggesting a link between receptor modulation and microbial community shifts. Molecular docking and gene expression analyses supported IMI interaction with TAS2Rs as a novel mechanism underlying pesticide-induced metabolic disruption. These findings illuminate the combined effects of diet and environmental chemicals on metabolism and identify intestinal taste receptors as potential therapeutic targets.