Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Life Sci. 2021 Apr 1;270:119037. doi: 10.1016/j.lfs.2021.119037. Epub 2021 Jan 23.
Skeletal muscle insulin resistance (SMIR) contributes to the metabolic syndrome. Mounting evidence has demonstrated that the second generation antipsychotic olanzapine causes SMIR. The present study sought to investigate the molecular mechanisms underlying olanzapine-induced SMIR.
Male rats were given olanzapine (5 mg/kg, by a gavage method) for consecutive eight weeks. Plasma glucose and insulin concentrations were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry.
Olanzapine increased fasting plasma insulin concentration, and decreased glucose clearance during insulin tolerance test in rats. In skeletal muscle, it decreased protein expression of membrane glucose transporter (GLUT) 4, the ratio of membrane to total GLUT4, and total insulin receptor substrate 1 (IRS1). However, it increased protein phosphorylation of Ser in IRS1, Y in phosphoinositide 3-kinase p85α and Ser in AKT. These results indicate olanzapine-induced impairment of skeletal muscle insulin signaling. Mechanistically, olanzapine upregulated mRNA expression of TNFα, IL6 and IL1β, and protein phosphorylation of both IκB kinase (IKK)α/β and nuclear factor (NF)κB p65. Furthermore, it increased protein phosphorylation of Ser in AMPKα2, whereas it decreased AMPKα2 activity. More importantly, both Western blot and immunohistochemical analyses revealed that olanzapine increased protein phosphorylation of Ser in protein kinase D1 (PKD1).
The present results suggest that the PKD1-mediated inflammatory pathway is involved in olanzapine-induced impairment of skeletal muscle insulin signaling in rats. Our findings may go new insight into the mechanisms underlying olanzapine-induced SMIR.
骨骼肌胰岛素抵抗（SMIR）是代谢综合征的发病机制之一。越来越多的证据表明，第二代抗精神病药奥氮平可导致 SMIR。本研究旨在探讨奥氮平诱导 SMIR 的分子机制。
雄性大鼠连续 8 周每天经灌胃给予奥氮平（5mg/kg）。采用酶法或 ELISA 法测定血浆葡萄糖和胰岛素浓度。采用实时 PCR、Western blot 和/或免疫组化法分析基因/蛋白表达。
奥氮平可增加大鼠空腹胰岛素浓度，并降低胰岛素耐量试验中葡萄糖清除率。在骨骼肌中，奥氮平降低了膜葡萄糖转运体（GLUT）4 的蛋白表达、膜与总 GLUT4 的比值和总胰岛素受体底物 1（IRS1）。然而，它增加了 IRS1 中 Ser 的磷酸化、磷酸肌醇 3-激酶 p85α 中 Y 的磷酸化和 AKT 中 Ser 的磷酸化。这些结果表明奥氮平诱导的骨骼肌胰岛素信号受损。在机制上，奥氮平上调了 TNFα、IL6 和 IL1β 的 mRNA 表达，以及 IKKα/β 和核因子（NF）κB p65 的磷酸化。此外，奥氮平还增加了 AMPKα2 中 Ser 的磷酸化，而降低了 AMPKα2 的活性。更重要的是，Western blot 和免疫组化分析均显示奥氮平增加了蛋白激酶 D1（PKD1）中 Ser 的磷酸化。
本研究结果提示，PKD1 介导的炎症通路可能参与了奥氮平诱导的大鼠骨骼肌胰岛素信号受损。我们的发现可能为奥氮平诱导的 SMIR 机制提供新的见解。
