Betahistine ameliorates olanzapine-induced weight gain through modulation of histaminergic, NPY and AMPK pathways

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 H-1 receptor agonist and H-3 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 H-1 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 AMPK alpha activation measured by the AMPK phosphorylation (pAMPK alpha)/AMPK alpha ratio compared with controls, whereas O + B co-treatment decreased the pAMPK alpha/AMPK alpha ratio, compared with olanzapine only treatment. The pAMPK alpha/AMPK alpha 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-pAMPK alpha pathways. (C) 2014 Elsevier Ltd. All rights reserved.