Table1_Olanzapine Promotes the Occurrence of Metabolic Disorders in Conditional TCF7L2-Knockout Mice.xlsx

Objectives: Schizophrenia (SCZ) patients display higher incidence of metabolic syndrome (MetS) and comorbidity of type II diabetes. Both atypical antipsychotics and genetic variants are believed to predispose the patients with the risk, but their interplay remains largely unknown. TCF7L2 is one of the most common genes strongly associated with glucose homeostasis which also participates in the pathogenesis of schizophrenia. In this study, we aimed to explore the regulatory roles of TCF7L2 in atypical antipsychotics-induced MetS.
Methods: Mice with pancreatic β-cell–specific Tcf7l2 deletion (CKO) were generated. The CKO mice and control littermates were subjected to olanzapine (4 mg/kg/day) or saline gavage for 6 weeks. Metabolic indices, β cell mass, and the expressing levels of TCF7L2 and GLP-1R in the pancreatic tissue were closely monitored.
Results: Tcf7l2 CKO mice displayed a spectrum of core features of MetS, which included remarkably increased rate of weight gain, higher fasting insulin, higher values of blood lipids (cholesterol, triglyceride, and low-density lipoprotein), impaired glucose tolerance, and hypertrophy of adipocytes. Notably, these effects could be further exacerbated by olanzapine. In addition, Tcf7l2 CKO mice with the olanzapine group showed significantly decreased expressions of GLP-1R protein and a trend of reduced pancreatic β-cell mass. RT-qPCR revealed that the CKO mice presented a significantly less transcription of Sp5, an important element of the Wnt signaling pathway.
Conclusion: Our study illustrates that mice with pancreatic β-cell–targeted Tcf7l2 deletion were more vulnerable to suffer metabolic abnormalities after olanzapine administration. This impairment may be mediated by the reduced expression of GLP-1R.

研究目的：精神分裂症（Schizophrenia, SCZ）患者的代谢综合征（Metabolic Syndrome, MetS）患病率与2型糖尿病（type II diabetes）共病率均显著升高。现有研究认为非典型抗精神病药物与遗传变异均可增加此类患者的发病风险，但二者的相互作用仍未明确。TCF7L2是与葡萄糖稳态密切相关的常见基因之一，同时也参与精神分裂症的发病过程。本研究旨在探讨TCF7L2在非典型抗精神病药物诱导的代谢综合征中的调控作用。
研究方法：构建胰腺β细胞特异性Tcf7l2敲除（CKO）小鼠模型。将CKO小鼠与同窝野生型对照小鼠分为两组，分别予以奥氮平（4 mg/kg/天）灌胃或生理盐水灌胃，持续6周。期间密切监测小鼠的代谢指标、β细胞质量，以及胰腺组织中TCF7L2与胰高血糖素样肽-1受体（Glucagon-Like Peptide-1 Receptor, GLP-1R）的表达水平。
研究结果：Tcf7l2 CKO小鼠表现出代谢综合征的一系列核心特征，包括体重增长率显著升高、空腹胰岛素水平上升、血脂（总胆固醇、甘油三酯与低密度脂蛋白）水平升高、糖耐量受损以及脂肪细胞肥大。值得注意的是，奥氮平可进一步加重上述代谢异常。此外，奥氮平干预的Tcf7l2 CKO小鼠的GLP-1R蛋白表达水平显著降低，同时胰腺β细胞质量呈下降趋势。RT-qPCR检测结果显示，CKO小鼠的Wnt信号通路重要元件Sp5的转录水平显著下调。
研究结论：本研究表明，胰腺β细胞特异性Tcf7l2敲除小鼠在奥氮平给药后更易出现代谢异常，该损伤效应可能通过GLP-1R表达下调介导。