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首页> 外文期刊>Endocrinology >Olanzapine-Activated AMPK Signaling in the Dorsal Vagal Complex Is Attenuated by Histamine H1 Receptor Agonist in Female Rats
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Olanzapine-Activated AMPK Signaling in the Dorsal Vagal Complex Is Attenuated by Histamine H1 Receptor Agonist in Female Rats

机译：组胺H1受体激动剂减弱雌性大鼠背迷走神经复合物中奥氮平激活的AMPK信号。

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摘要

Weight gain and its related metabolic disorders are major side effects associated with second generation antipsychotic drug treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of olanzapine treatment (8, 16, and 36 d) on DVC AMPK signaling in olanzapine-induced weight gain and whether these changes are associated with olanzapine- induced H1 receptor antagonism. During the 8-day olanzapine treatment, the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK(pAMPK) (activated AMPK) as well as its directly downstream phospho-acetyl-coenzyme A carboxylase was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36 d of olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1 receptor protein expression was not significantly altered by olanzapine, the pAMPK expression was significantly positively correlated with the H1 receptor level after the 8-, 16-, and 36-day olanzapine treatments. Moreover, we showed that an H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in olanzapine-induced obesity. Thus, olanzapine- induced DVC AMPK activation may be at least partially related to olanzapine's antagonistic effect on the H1 receptor.
机译：体重增加及其相关的代谢紊乱是第二代抗精神病药治疗的主要副作用。背迷走神经复合体（DVC）和AMP激活的蛋白激酶（AMPK）与食物摄入和体重的调节有关。阻断组胺H1受体有助于抗精神病药引起的体重增加。本研究调查了奥氮平治疗（8、16和36 d）对DVC AMPK信号在奥氮平诱导的体重增加中的时间依赖性作用，以及这些变化是否与奥氮平诱导的H1受体拮抗作用有关。在为期8天的奥氮平治疗期间，大鼠食欲亢进，体重迅速增加。 AMPK（pAMPK）（活化的AMPK）及其直接下游的磷酸-乙酰辅酶A羧化酶的磷酸化显着增加。 pAMPK / AMPK比是AMPK活性的指标，与饲喂效率和体重增加呈显着正相关。随着治疗时间的延长（奥氮平治疗16天和36天），大鼠不再肥大，DVC AMPK信号传导也不再发生任何变化。尽管奥氮平不会显着改变DVC H1受体蛋白的表达，但在8天，16天和36天奥氮平治疗后，pAMPK表达与H1受体水平显着正相关。此外，我们表明，H1受体激动剂2-（3-三氟甲基苯基）组胺以剂量依赖的方式显着抑制了奥氮平诱导的食欲亢进和DVC AMPK激活。这些结果表明DVC AMPK在奥氮平诱发的肥胖中具有时间依赖性。因此，奥氮平诱导的DVC AMPK激活可能至少部分与奥氮平对H1受体的拮抗作用有关。

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