title: Betahistine ameliorates olanzapine-induced weight gain through modulation of histaminergic, NPY and AMPK pathways.
abstract: Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of olanzapine and betahistine (O+B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O+B co-treatment significantly downregulated the H1R levels, compared to the olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by olanzapine, but it was significantly reversed by O+B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio, compared with olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although olanzapine administration decreased the POMC mRNA level, this level was not affected by O+B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522 NSW, Australia; Centre for Translational Neuroscience, School of Medicine, 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, University of Wollongong, Wollongong, 2522 NSW, Australia; Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst, 2010 NSW, Australia.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522 NSW, Australia.
authors.forename: Nagesh
authors.initials: N
authors.lastname: Pai
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522 NSW, Australia; Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522 NSW, Australia; Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst, 2010 NSW, Australia. Electronic address: chao@uow.edu.au.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects*; D001621:Betahistine / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D005260:Female; D006632:Histamine / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology*; D009478:Neuropeptide Y / Q000378:metabolism; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D014150:Antipsychotic Agents; D017442:Histamine Agonists; D009478:Neuropeptide Y; D001569:Benzodiazepines; D006632:Histamine; D000263:Adenylate Kinase; D000077152:Olanzapine; D001621:Betahistine
keywords: AMP-activated protein kinase; Betahistine; Body weight gain; Food intake; Histamine H(1) receptors; Neuropeptide Y; Olanzapine