Second generation antipsychotics, particularly olanzapine, induce severe obesity, which is associated with their antagonistic effect on the histamine H1 receptor (H1R). We have previously demonstrated that oral administration of olanzapine increases the concentration of neuropeptide Y (NPY) in the hypothalamus of rats, accompanied by hyperphagia and weight gain. However, it is unclear if the increased NPY after olanzapine administration is due to its direct effect on hypothalamic neurons and its H1R antagonistic property. In the present study, we showed that with an inverted U-shape dose-response curve, olanzapine increased NPY expression in the NPY-GFP hypothalamic neurons; however, this was not the case in the hypothalamic neurons of H1R knockout mice. Olanzapine inhibited the interaction of H1R and GHSR1a (ghrelin receptor) in the primary mouse hypothalamic neurons and NPY-GFP neurons examined by confocal fluorescence resonance energy transfer (FRET) technology. Furthermore, an H1R agonist, FMPH inhibited olanzapine activation of GHSR1a downstream signaling pAMPK and transcription factors of NPY (pFOXO1 and pCREB) in the hypothalamic NPY-GFP cell. However, an olanzapine analogue (E-Olan) with lower affinity to H1R presented negligible enhancement of pCREB within the nucleus of NPY neurons. These findings suggest that the H1R antagonist property of olanzapine inhibits the interaction of H1R and GHSR1a, activates GHSR1a downstream signaling pAMPK-FOXO1/pCREB and increases hypothalamic NPY: this could be one of the important molecular mechanisms of H1R antagonism of olanzapine-induced obesity in antipsychotic management of psychiatric disorders.

中文翻译：

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奥氮平通过破坏小鼠下丘脑神经元中的 H1R-GHSR1a 相互作用来增加 AMPK-NPY 促食欲信号

第二代抗精神病药，尤其是奥氮平，会导致严重肥胖，这与其对组胺 H1 受体 (H1R) 的拮抗作用有关。我们之前已经证明，口服奥氮平会增加大鼠下丘脑中神经肽 Y (NPY) 的浓度，并伴有食欲亢进和体重增加。然而，尚不清楚奥氮平给药后 NPY 的增加是否是由于其对下丘脑神经元的直接影响及其 H1R 拮抗特性。在本研究中，我们发现奥氮平通过倒 U 形剂量反应曲线增加了 NPY-GFP 下丘脑神经元中 NPY 的表达；然而，H1R 基因敲除小鼠的下丘脑神经元并非如此。通过共聚焦荧光共振能量转移 (FRET) 技术检测，奥氮平抑制原代小鼠下丘脑神经元和 NPY-GFP 神经元中 H1R 和 GHSR1a（生长素释放肽受体）的相互作用。此外，H1R 激动剂 FMPH 抑制了下丘脑 NPY-GFP 细胞中 GHSR1a 下游信号传导 pAMPK 和 NPY 转录因子（pFOXO1 和 pCREB）的奥氮平激活。然而，对 H1R 具有较低亲和力的奥氮平类似物 (E-Olan) 对 NPY 神经元核内 pCREB ​​的增强作用可忽略不计。这些发现表明奥氮平的 H1R 拮抗剂特性抑制 H1R 和 GHSR1a 的相互作用，激活 GHSR1a 下游信号 pAMPK-FOXO1/pCREB ​​并增加下丘脑 NPY：