title: Hypothalamic histamine H1 receptor-AMPK signaling time-dependently mediates olanzapine-induced hyperphagia and weight gain in female rats.
abstract: Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1-12: early acceleration, day 13-28: middle new equilibrium, and day 29-36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity.
authors.affiliation: Centre for Translational Neuroscience, School of Medicine and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522, NSW, Australia.
authors.forename: Meng
authors.initials: M
authors.lastname: He
authors.affiliation: Centre for Translational Neuroscience, School of Medicine and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522, NSW, Australia.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Centre for Translational Neuroscience, School of Medicine and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522, NSW, Australia; Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst 2010, NSW, Australia.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.affiliation: Centre for Translational Neuroscience, School of Medicine and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522, NSW, Australia.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Centre for Translational Neuroscience, School of Medicine and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522, NSW, Australia.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Lian
authors.affiliation: Centre for Translational Neuroscience, School of Medicine and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522, NSW, Australia; Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst 2010, NSW, Australia. Electronic address: xhuang@uow.edu.au.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D005260:Female; D006963:Hyperphagia / Q000139:chemically induced / Q000378:metabolism*; D000077152:Olanzapine; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects* / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D011969:Receptors, Histamine H1; D001569:Benzodiazepines; D000263:Adenylate Kinase; D000077152:Olanzapine
keywords: AMP-activated protein kinase; Antipsychotics; Food intake; Histamine H1 receptor; Olanzapine; Weight gain