Yang Ye, Shen Manjun, Li Li, Long Yujun, Wang Lu, Lang Bing, Wu Renrong
National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China.
Shenzhen Nanshan Center for Chronic Disease Control, Department of Psychiatry, Shenzhen, China.
Front Cell Dev Biol. 2022 Jul 6;10:890472. doi: 10.3389/fcell.2022.890472. eCollection 2022.
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. 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. 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. 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.
精神分裂症（SCZ）患者代谢综合征（MetS）的发病率较高，且常合并II型糖尿病。非典型抗精神病药物和基因变异都被认为会使患者面临这种风险，但其相互作用在很大程度上仍不清楚。TCF7L2是与葡萄糖稳态密切相关的最常见基因之一，它也参与精神分裂症的发病机制。在本研究中，我们旨在探讨TCF7L2在非典型抗精神病药物诱导的MetS中的调节作用。我们构建了胰腺β细胞特异性Tcf7l2缺失（CKO）的小鼠。将CKO小鼠和对照同窝小鼠用奥氮平（4mg/kg/天）或生理盐水灌胃6周。密切监测代谢指标、β细胞质量以及胰腺组织中TCF7L2和GLP-1R的表达水平。Tcf7l2 CKO小鼠表现出一系列MetS的核心特征，包括体重增加率显著提高、空腹胰岛素水平升高、血脂（胆固醇、甘油三酯和低密度脂蛋白）值升高、糖耐量受损以及脂肪细胞肥大。值得注意的是，奥氮平会进一步加剧这些影响。此外，奥氮平组的Tcf7l2 CKO小鼠GLP-1R蛋白表达显著降低，胰腺β细胞质量有减少的趋势。RT-qPCR显示，CKO小鼠中Wnt信号通路的重要元件Sp5的转录显著减少。我们的研究表明，胰腺β细胞靶向Tcf7l2缺失的小鼠在给予奥氮平后更容易出现代谢异常。这种损害可能是由GLP-1R表达降低介导的。
