抄録
Cumulative evidence has suggested that blockage of dopamine receptors,especially a dopamine D2 receptor (D2R), by antipsychotics, causes metabolic abnormalities. Adipose tissue insulin resistance (Adipo-IR), resulting in excessive over-releasing free fatty acids from adipose tissue, contributes to development and progress of systemic metabolic abnormalities and fatty liver. Sulpiride is an old antipsychotics that is still frequently used in many developing countries. However,its adverse metabolic effects remain poorly understood. Here, chronic administration of sulpiride (80 mg/kg, subcutaneously, once daily, 6 weeks) increased fasting insulin concentration and the index of the homeostasis model assessment of insulin resistance in rats. More importantly, sulpiride increased hepatic triglyceride accumulation and the Oil Red O-stained area. Gene expression profile revealed that sulpiride did not alter hepatic mRNA and protein expression of sterol regulatory element-binding protein and carbohydrate-response element-binding protein, two important transcript factors responsible for hepatic de novo lipid synthesis. In contrast, sulpiride induced Adipo-IR-associated changes,such as increases in plasma non-esterified fatty acid concentrations at the baseline and during oral glucose tolerance test,the Adipo-IR index and adipocyte size. Marked decrease in adipose mRNA and protein expression of insulin receptor substrate (IRS)-1,but not IRS-2, further confirmed sulpiride-induced Adipo-IR. Co-administration of bromocriptine (a D2R agonist) attenuated sulpiride-induced hyperprolactinemia, but it was without effect on insulin resistance and fatty liver. Therefore, the present results suggest that Adipo-IR plays an important role in sulpiride-induced D2R-independent fatty liver in rats. Our findings may provide new insights into the mechanisms underlying the adverse effects of the old antipsychotics.
