Olanzapine increases AMPK-NPY orexigenic signaling by disrupting H1R-GHSR1a interaction in the hypothalamic neurons of mice

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dc.contributor.authorChen, X.
dc.contributor.authorYu, Y.
dc.contributor.authorZheng, P.
dc.contributor.authorJin, T.
dc.contributor.authorHe, M.
dc.contributor.authorZheng, M.
dc.contributor.authorSong, X.
dc.contributor.authorJones, A.
dc.contributor.authorHuang, X.F.
dc.date.issued2020
dc.description.abstractSecond 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.
dc.description.statementofresponsibilityXiaoqi Chena, Yinghua Yu, Peng Zheng, Tiantian Jin, Meng He, Mingxuan Zheng, Xueqin Song, Alison Jones, Xu-Feng Huang
dc.identifier.citationPsychoneuroendocrinology, 2020; 114:104594-1-104594-10
dc.identifier.doi10.1016/j.psyneuen.2020.104594
dc.identifier.issn0306-4530
dc.identifier.issn1873-3360
dc.identifier.orcidJones, A. [0000-0002-1105-6195]
dc.identifier.urihttps://hdl.handle.net/2440/139192
dc.language.isoen
dc.publisherElsevier BV
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1176503
dc.rights© 2020 Elsevier Ltd. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.psyneuen.2020.104594
dc.subjectAntipsychotic drug; Histamine H1 receptor; Neuropeptide Y; Hypothalamus; Ghrelin receptor 1a; Weight gain; BMI
dc.subject.meshHypothalamus
dc.subject.meshNeurons
dc.subject.meshAnimals
dc.subject.meshMice, Knockout
dc.subject.meshMice
dc.subject.meshWeight Gain
dc.subject.meshNeuropeptide Y
dc.subject.meshReceptors, Histamine H1
dc.subject.meshHistamine H1 Antagonists
dc.subject.meshAntipsychotic Agents
dc.subject.meshSignal Transduction
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshReceptors, Ghrelin
dc.subject.meshAMP-Activated Protein Kinases
dc.subject.meshOlanzapine
dc.titleOlanzapine increases AMPK-NPY orexigenic signaling by disrupting H1R-GHSR1a interaction in the hypothalamic neurons of mice
dc.typeJournal article
pubs.publication-statusPublished

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