Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats
Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats
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DOI：
10.1038/s41401-021-00680-x
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发表时间：
2021-05-11
影响因子：
8.2
通讯作者：
Hu, Chang-hua
中科院分区：
文献类型：
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作者：
Li, De-juan;Yue, Qin;Hu, Chang-hua
布雷哌唑（Bre）是2015年美国FDA批准的一种新型多靶点抗精神病药（APD），显示出良好的治疗潜力。但它缺乏对代谢副作用的评估，这阻碍了精神分裂症的治疗。胰高血糖素样肽 1 (GLP1) 是一种与胰岛素作用和代谢相关的肠促胰岛素，与大多数 APD 引起的代谢综合征 (MS) 有关。在这项研究中，我们检查了 Bre 对大鼠糖脂代谢的不利影响，并确定 GLP1 是否参与 Bre 引起的 MS。在实验的第一部分中，大鼠口服Bre（0.5 mg中心点kg（-1）中心点d（-1））28天，阿立哌唑（1.0 mg中心点kg（-1）中心点d（-1））或奥氮平（1.0 mg中心点kg（-1）中心点d（-1））作为对照。与媒介物相比，Bre给药显着增加了体重增加、血脂（TG、TC、LDL、FFA）和血糖水平，并伴有激素（胰岛素、胰高血糖素、GLP1）失衡以及糖耐量和胰岛素敏感性受损。此外，我们证明，Bre 给药通过抑制 CaMKII α、AMPK 和 β-catenin 显着降低胰腺和小肠中 GLP1 的蛋白和 mRNA 水平。 Bre 给药还会引起胰岛功能障碍，导致胰腺中 GLP1R、PI3K、IR beta 表达减少，以及肝脏和骨骼肌中 IRS1、PI3K、p-AKT 和 GLUT4 表达的干扰，这代表胰岛素抵抗。在实验的第二部分中，大鼠口服Bre（0.5 mg中心点kg(-1)中心点d(-1)）42天。我们发现，与GLP1受体（GLP1R）激动剂利拉鲁肽（0.125mg中心点kg(-1)中心点d(-1)，腹膜内注射）共同给药可以改善Bre引起的代谢异常。我们的结果表明，GLP1/GLP1R 信号传导参与 Bre 诱导的糖脂代谢紊乱，与利拉鲁肽联合治疗是针对这些异常代谢的有效干预措施。
Brexpiprazole (Bre) is a new multi-target antipsychotic drug (APD) approved by the US FDA in 2015, and shows good therapeutic potential. But it lacks assessments on the metabolic side effects, which obstructs the treatment of schizophrenia. Glucagon-like peptide 1 (GLP1), an incretin associated with insulin action and metabolism, is involved in the metabolic syndrome (MS) caused by most APDs. In this study, we examined the adverse effects of Bre on glycolipid metabolism in rats and determined whether GLP1 was involved in Bre-caused MS. In the first part of experiments, rats were orally administered Bre (0.5 mg center dot kg(-1)center dot d(-1)) for 28 days with aripiprazole (1.0 mg center dot kg(-1)center dot d(-1)) or olanzapine (1.0 mg center dot kg(-1)center dot d(-1)) as the controls. Compared to vehicle, Bre administration significantly increased the weight gain, serum lipid (TG, TC, LDL, FFA), and blood glucose levels accompanied by the hormonal (insulin, glucagon, GLP1) imbalance, and the impaired glucose tolerance and insulin sensitivity. Moreover, we demonstrated that Bre administration significantly decreased the protein and mRNA levels of GLP1 in pancreas and small intestine by suppressing CaMKII alpha, AMPK, and beta-catenin; Bre administration also caused islet dysfunction with decreased GLP1R, PI3K, IR beta expression in pancreas, and the interference of IRS1, PI3K, p-AKT, and GLUT4 expression in the liver and skeletal muscle that represented the insulin resistance. In the second part of experiments, rats were orally administered Bre (0.5 mg center dot kg(-1)center dot d(-1)) for 42 days. We showed that co-administration with the GLP1 receptor (GLP1R) agonist liraglutide (0.125 mg center dot kg(-1)center dot d(-1), ip) could ameliorate Bre-caused metabolic abnormalities. Our results demonstrate that GLP1/GLP1R signaling is involved in Bre-induced glycolipid metabolic disorders and co-treatment with liraglutide is an effective intervention against those abnormal metabolisms.