Abstract
Although antipsychotics are established drugs in schizophrenia treatment, they are admittedly known to induce side effects favoring the onset of obesity and worsening its complications. Despite potential involvement of histamine receptor antagonism, or of other neurotransmitter systems, the mechanism by which antipsychotic drugs increase body weight is not elucidated. The aim of the present study was to investigate whether chronic antipsychotic treatments can directly alter the regulation of two main functions of white adipose tissue: lipolysis and glucose utilization. The influence of a classical antipsychotic (haloperidol) was compared to that of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (ziprasidone). Cell size, lipolytic capacity and glucose transport activity were determined in white adipocytes of rats subjected to 5-week oral treatment with these antipsychotics. Gene expression of adipocyte proteins involved in glucose transport or fat storage and mobilization, such as glucose transporters (GLUT1 and GLUT4), leptin, matrix metallo-proteinase-9 (MMP9), hormone-sensitive lipase (HSL) and fatty acid synthase (FAS) was also evaluated. Adipocytes from chronic olanzapine-treated rats exhibited decreased lipolytic activity, lowered HSL expression and increased FAS expression. These changes were concomitant to enlarged fat deposition and adipocyte size. Alterations were observed in adipocytes from olanzapine-treated rats whereas the other antipsychotics did not induce any notable disorder. Our results therefore show evidence of an effect of chronic antipsychotic treatment on rat adipocyte metabolism. Thus, impairment of fat cell lipolysis should be considered as a side effect of certain antipsychotics, leading, along with the already documented hyperphagia, to the excessive weight gain observed in patients under prolonged treatment.
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Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686–1696.
Eder U, Mangweth B, Ebenbichler C, Weiss E, Hofer A, Hummer M et al. Association of olanzapine-induced weight gain with an increase in body fat. Am J Psychiatry 2001; 158: 1719–1722.
Wirshing DA, Wirshing WC, Kysar L, Berisford MA, Goldstein D, Pashdag J et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999; 60: 358–363.
Haupt DW, Newcomer JW . Hyperglycemia and antipsychotic medications. J Clin Psychiatry 2001; 62: 15–26; discussion 40–41.
Wirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing WC . The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry 2002; 63: 856–865.
Basile VS, Masellis M, McIntyre RS, Meltzer HY, Lieberman JA, Kennedy JL . Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. J Clin Psychiatry 2001; 62: 45–66.
Itowi N, Nagai K, Nakagawa H, Watanabe T, Wada H . Changes in the feeding behavior of rats elicited by histamine infusion. Physiol Behav 1988; 44: 221–226.
Lecklin A, Etu-Seppala P, Stark H, Tuomisto L . Effects of intracerebroventricularly infused histamine and selective H1, H2 and H3 agonists on food and water intake and urine flow in Wistar rats. Brain Res 1998; 793: 279–288.
Morimoto T, Yamamoto Y, Yamatodani A . Brain histamine and feeding behavior. Behav Brain Res 2001; 124: 145–150.
Kudoh A, Ishihara H, Matsuki A . Pituitary–adrenal and parasympathetic function in chronic schizophrenic patients with postoperative ileus or hypotension. Neuropsychobiology 1999; 39: 125–130.
Yoshimatsu H, Tsuda K, Niijima A, Tatsukawa M, Chiba S, Sakata T . Histidine induces lipolysis through sympathetic nerve in white adipose tissue. Eur J Clin Invest 2002; 32: 236–241.
Lafontan M, Bousquet-Melou A, Galitzky J, Barbe P, Carpéné C, Langin D et al. Adrenergic receptors and fat cells: differential recruitment by physiological amines and homologous regulation. Obes Res 1995; 3: 507S–514S.
Cannon B, Nedergaard J . Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84: 277–359.
Ashby Jr CR, Wang RY . Pharmacological actions of the atypical antipsychotic drug clozapine: a review. Synapse 1996; 24: 349–394.
Bymaster FP, Hemrick-Luecke SK, Perry KW, Fuller RW . Neurochemical evidence for antagonism by olanzapine of dopamine, serotonin, alpha 1-adrenergic and muscarinic receptors in vivo in rats. Psychopharmacology (Berlin) 1996; 124: 87–94.
Baptista T, de Baptista EA, Lalonde J, Plamondon J, Kin NM, Beaulieu S et al. Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 1305–1311.
Baptista T, Araujo de Baptista E, Ying Kin NM, Beaulieu S, Walker D, Joober R et al. Comparative effects of the antipsychotics sulpiride or risperidone in rats. I: bodyweight, food intake, body composition, hormones and glucose tolerance. Brain Res 2002; 957: 144–151.
Goudie AJ, Smith JA, Halford JC . Characterization of olanzapine-induced weight gain in rats. J Psychopharmacol 2002; 16: 291–296.
Pouzet B, Mow T, Kreilgaard M, Velschow S . Chronic treatment with antipsychotics in rats as a model for antipsychotic-induced weight gain in human. Pharmacol Biochem Behav 2003; 75: 133–140.
Minet-Ringuet J, Even PC, Lacroix M, Tomé D, de Beaurepaire R . A model for antipsychotic-induced obesity in the male rat. Psychopharmacology 2006; 187: 447–454.
Reeves PG, Nielsen FH, Fahey Jr GC . AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 1993; 123: 1939–1951.
Rodbell M . Localization of lipoprotein lipase in fat cells of rat adipose tissue. J Biol Chem 1964; 239: 753–755.
Honnor RC, Dhillon GS, Londos C . cAMP-dependent protein kinase and lipolysis in rat adipocytes. I. Cell preparation, manipulation, and predictability in behavior. J Biol Chem 1985; 260: 15122–15129.
Wieland O . Enzymic method for the determination of glycerin. Biochem Z 1957; 329: 313–319.
Dole VP, Meinertz H . Microdetermination of long-chain fatty acids in plasma and tissues. J Biol Chem 1960; 235: 2595–2599.
Olefsky JM . Mechanisms of the ability of insulin to activate the glucose-transport system in rat adipocytes. Biochem J 1978; 172: 137–145.
Carpéné C, Chalaux E, Lizarbe M, Estrada A, Mora C, Palacin M et al. Beta 3-adrenergic receptors are responsible for the adrenergic inhibition of insulin-stimulated glucose transport in rat adipocytes. Biochem J 1993; 296: 99–105.
Le Lay S, Krief S, Farnier C, Lefrere I, Le Liepvre X, Bazin R et al. Cholesterol, a cell size-dependent signal that regulates glucose metabolism and gene expression in adipocytes. J Biol Chem 2001; 276: 16904–16910.
Enrique-Tarancon G, Marti L, Morin N, Lizcano JM, Unzeta M, Sevilla L et al. Role of semicarbazide-sensitive amine oxidase on glucose transport and GLUT4 recruitment to the cell surface in adipose cells. J Biol Chem 1998; 273: 8025–8032.
Minet-Ringuet J, Even PC, Guesdon B, Tomé D, de Beaurepaire R . Effects of chronic neuroleptic treatments on nutrient selection, body weight, and body composition in the male rat under dietary self-selection. Appetite 2006; 46: 254–262.
Baptista T, Contreras Q, Teneud L, Albornoz MA, Acosta A, Paez X et al. Mechanism of the neuroleptic-induced obesity in female rats. Prog Neuropsychopharmacol Biol Psychiatry 1998; 22: 187–198.
Arjona AA, Zhang SX, Adamson B, Wurtman RJ . An animal model of antipsychotic-induced weight gain. Behav Brain Res 2004; 152: 121–127.
Kaur G, Kulkarni SK . Studies on modulation of feeding behavior by atypical antipsychotics in female mice. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 277–285.
Thornton-Jones Z, Neill JC, Reynolds GP . The atypical antipsychotic olanzapine enhances ingestive behaviour in the rat: a preliminary study. J Psychopharmacol 2002; 16: 35–37.
Virkkunen M, Wahlbeck K, Rissanen A, Naukkarinen H, Franssila-Kallunki A . Decrease of energy expenditure causes weight increase in olanzapine treatment – a case study. Pharmacopsychiatry 2002; 35: 124–126.
Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M et al. Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am J Psychiatry 1999; 156: 312–314.
Souza SC, Muliro KV, Liscum L, Lien P, Yamamoto MP, Schaffer JE et al. Modulation of hormone-sensitive lipase and protein kinase A-mediated lipolysis by perilipin A in an adenoviral reconstituted system. J Biol Chem 2002; 277: 8267–8272.
Martinez-Botas J, Anderson JB, Tessier D, Lapillonne A, Chang BH, Quast MJ et al. Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nat Genet 2000; 26: 474–479.
Poyurovsky M, Isaacs I, Fuchs C, Schneidman M, Faragian S, Weizman R et al. Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study. Am J Psychiatry 2003; 160: 297–302.
Duncan GE, Zorn S, Lieberman JA . Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses in schizophrenia. Mol Psychiatry 1999; 4: 418–428.
Engl J, Laimer M, Niederwanger A, Kranebitter M, Starzinger M, Pedrini MT et al. Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells. Mol Psychiatry 2005; 10: 1089–1096.
Robinson KA, Yacoub Wasef SZ, Buse MG . At therapeutic concentrations, olanzapine does not affect basal or insulin-stimulated glucose transport in 3T3-L1 adipocytes. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 93–98.
Vestri HS, Maianu L, Moellering DR, Garvey WT . Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis. Neuropsychopharmacology 2006 [E-pub ahead of print].
Acknowledgements
This study was supported by a grant from Pfizer (New York). Julie Minet-Ringuet was supported by a grant from La Fondation pour la Recherche Médicale. We thank Brooke Maddux for re-reading and correcting the manuscript.
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Minet-Ringuet, J., Even, P., Valet, P. et al. Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Mol Psychiatry 12, 562–571 (2007). https://doi.org/10.1038/sj.mp.4001948
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DOI: https://doi.org/10.1038/sj.mp.4001948
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