Antipsychotic-induced weight gain is a well-established but poorly understood clinical phenomenon. New mechanistic insights into how antipsychotics modulate adipose physiology are sorely needed, in hopes of either devising a therapeutic intervention to ameliorate weight gain or contributing to improved design of future agents. In this study, we have hypothesized that the weight gain-associated tricyclic antipsychotics clozapine and chlorpromazine directly impact adipose tissue by potentiating adipogenic differentiation of preadipocytes. Utilizing a well-established in vitro model system (3T3-L1 preadipocyte cell line), we demonstrate that, when applied specifically during induction of adipogenic differentiation, both clozapine and chlorpromazine significantly potentiate in vitro adipogenesis, observed as morphological changes and increased intracellular lipid accumulation. These persistent effects, observed at endpoints well after the end of antipsychotic exposure, are accompanied by increased transcript- and protein-level expression of the mature adipocyte marker perilipin-1, as indicated by RT-qPCR and Western blotting, but not by further upregulation of pro-adipogenic transcription factors versus positive controls. Our findings point to a possible physiological mechanism of antipsychotic-induced hyperplasia, with potentiated expression of mature adipocyte markers enhancing the differentiation and maturation of preadipocytes.

中文翻译：

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三环类抗精神病药促进脂肪基因表达以增强体外前脂肪细胞分化。

抗精神病药引起的体重增加是一种公认​​但知之甚少的临床现象。迫切需要对抗精神病药物如何调节脂肪生理学的新机制见解，希望设计一种治疗干预措施来改善体重增加或有助于改进未来药物的设计。在这项研究中，我们假设与体重增加相关的三环类抗精神病药氯氮平和氯丙嗪通过增强前脂肪细胞的成脂分化直接影响脂肪组织。利用完善的体外模型系统（3T3-L1 前脂肪细胞系），我们证明，当专门用于诱导脂肪形成分化时，氯氮平和氯丙嗪均显着增强体外脂肪生成，观察到形态变化和细胞内脂质积累增加。RT-qPCR 和蛋白质印迹表明，这些持续效应在抗精神病药物暴露结束后的终点很长时间内观察到，伴随着成熟脂肪细胞标志物 perilipin-1 的转录和蛋白质水平表达增加，但没有进一步上调促脂肪形成转录因子与阳性对照的比较。我们的研究结果指出了抗精神病药诱导的增生的可能生理机制，成熟脂肪细胞标志物的增强表达增强了前脂肪细胞的分化和成熟。伴随着成熟脂肪细胞标志物 perilipin-1 的转录水平和蛋白质水平表达增加，如 RT-qPCR 和蛋白质印迹所示，但与阳性对照相比，促脂肪形成转录因子的进一步上调并未出现。我们的研究结果指出了抗精神病药诱导的增生的可能生理机制，成熟脂肪细胞标志物的增强表达增强了前脂肪细胞的分化和成熟。伴随着成熟脂肪细胞标志物 perilipin-1 的转录水平和蛋白质水平表达增加，如 RT-qPCR 和蛋白质印迹所示，但与阳性对照相比，促脂肪形成转录因子的进一步上调并未出现。我们的研究结果指出了抗精神病药诱导的增生的可能生理机制，成熟脂肪细胞标志物的增强表达增强了前脂肪细胞的分化和成熟。