Abstract
Olanzapine is known to be advantageous with respect to outcome and drug compliance in patients with schizophrenia. However, olanzapine has adverse effects, including a higher incidence of weight gain and metabolic disturbances, when compared with those of other antipsychotic agents. The mechanisms underlying these adverse events remain obscure. Female rats were orally administered olanzapine (2 mg/kg) or vehicle once a day for 2 weeks to ascertain if hypothalamic AMP-activated protein kinase (AMPK) mediates olanzapine-induced weight gain and hyperphagia. Body weight and food intake in each rat were evaluated every day and every two days, respectively. After the termination of drug treatment, we measured the protein levels of AMPK and phosphorylated AMPK in the hypothalamus using western blot analyses. Olanzapine significantly increased body weight and food intake. The phosphorylation levels of AMPK were significantly elevated by olanzapine. These results suggest that activation of hypothalamic AMPK may mediate hyperphagia and weight gain induced by chronic treatment with olanzapine.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B, Lynch CJ (2006) Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity 14(1):36–51
Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC et al (1999) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156:1686–1696
Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ (2004) AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279(13):12005–12008
Arjona AA, Zhang SX, Adamson B, Wurtman R (2004) An animal model of antipsychotic-induced weight gain. Behav Brain Res 152:121–127
Baptista T, Martínez J, Lacruz A, Rangel N, Beaulieu S, Serrano A, Arapé Y, Martinez M, de Mendoza S, Teneud L, Hernández L (2006) Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial. Can J Psychiatry 51:192–196
Chau-Van C, Gamba M, Salvi R, Gaillard RC, Pralong FP (2007) Metformin inhibits adenosine 5′-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology 148(2):507–511
Choi S, DiSilvio B, Unangst J, Fernstrom JD (2007) Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats. Life Sci 81(12):1024–1030
Coccurello R, Caprioli A, Ghirardi O, Conti R, Ciani B, Daniele S, Bartolomucci A, Moles A (2006) Chronic administration of olanzapine induces metabolic and food intake alterations: a mouse model of the atypical antipsychotic-associated adverse effects. Psychopharmacology 186(4):561–571
Cooper GD, Pickavance LC, Wilding JP, Halford JC, Goudie AJ (2005) A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology 181(1):80–89
Davoodi N, Kalinichev M, Korneev SA, Clifton PG (2009) Hyperphagia and increased meal size are responsible for weight gain in rats treated sub-chronically with olanzapine. Psychopharmacology 203(4):693–702
Deng C, Weston-Green K, Huang XF (2010) The role of histaminergic H1 and h3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain? Prog Neuropsychopharmacol Biol Psychiatry 34(1):1–4
Kalinichev M, Rourke C, Daniels AJ, Grizzle MK, Britt CS, Ignar DM, Jones DN (2005) Characterisation of olanzapine-induced weight gain and effect of aripiprazole vs olanzapine on body weight and prolactin secretion in female rats. Psychopharmacology 182(2):220–231
Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, Lee IK, Viollet B, Youn JH, Lee HK, Lee KU (2004) Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med 10(7):727–733
Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH (2007) Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci USA 104(9):3456–3459
Kirk SL, Glazebrook J, Grayson B, Neill JC, Reynolds GP (2009) Olanzapine-induced weight gain in the rat: role of 5-HT2C and histamine H1 receptors. Psychopharmacology 207(1):119–125
Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T, Suzuki R, Satoh H, Tsuchida A, Moroi M, Sugi K, Noda T, Ebinuma H, Ueta Y, Kondo T, Araki E, Ezaki O, Nagai R, Tobe K, Terauchi Y, Ueki K, Minokoshi Y, Kadowaki T (2007) Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6(1):55–68
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (2009) Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373:31–41
Lieberman JA, Stroup TS, McEvoy JP et al (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223
Martins PJ, Haas M, Obici S (2010) Central nervous system delivery of the antipsychotic olanzapine induces hepatic insulin resistance. Diabetes 59(10):2418–2425
Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferré P, Birnbaum MJ, Stuck BJ, Kahn BB (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574
Starrenburg FCJ, Bogers JPAM (2009) How can antipsychotics cause diabetes mellitus? Insight based on receptor-binding profiles, humoral factors and transporter proteins. Eur Psychiatry 24:164–170
Wu RR, Zhao JP, Jin H, Shao P, Fang MS, Guo XF, He YQ, Liu YJ, Chen JD, Li LH (2008) Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA 299(2):185–193
Yoon S, Noh JS, Choi SY, Baik JH (2010) Effects of atypical antipsychotic drugs on body weight and food intake in dopamine D2 receptor knockout mice. Biochem Biophys Res Commun 393(2):235–241
Acknowledgments
This study was supported in part by the Grants-in-Aid for Scientific Research [(B) 17390159], the Grants-in-Aid for Young Scientists [(Start-up) 18890227 and (Start-up) 20800066], and the Grants-in-Aid for Young Scientists [(B) 19790199, (B) 21790102, (B) 21790255, (B) 21790257, and (B) 21790526] from JSPS, Japan, the Ministry of Health, Labour and Welfare of Japan (H19-nanchi-ippan-006), the Nakatomi Foundation, Research Foundation ITSUU Laboratory, and the Kakihara Science and Technology Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sejima, E., Yamauchi, A., Nishioku, T. et al. A Role for Hypothalamic AMP-Activated Protein Kinase in the Mediation of Hyperphagia and Weight Gain Induced by Chronic Treatment with Olanzapine in Female Rats. Cell Mol Neurobiol 31, 985–989 (2011). https://doi.org/10.1007/s10571-011-9663-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-011-9663-8