Abstract
Olanzapine and other atypical antipsychotics cause metabolic side effects leading to obesity and diabetes; although these continue to be an important public health concern, their underlying mechanisms remain elusive. Therefore, an animal model of these side effects was developed in male Sprague–Dawley rats. Chronic administration of olanzapine elevated fasting glucose, impaired glucose and insulin tolerance, increased fat mass but, in contrast to female rats, did not increase body weight or food intake. Acute studies were conducted to delineate the mechanisms responsible for these effects. Olanzapine markedly decreased physical activity without a compensatory decline in food intake. It also acutely elevated fasting glucose and worsened oral glucose and insulin tolerance, suggesting that these effects are adiposity independent. Hyperinsulinemic-euglycemic clamp studies measuring 14C-2-deoxyglucose uptake revealed tissue-specific insulin resistance. Insulin sensitivity was impaired in skeletal muscle, but either unchanged or increased in adipose tissue depots. Consistent with the olanzapine-induced hyperglycemia, there was a tendency for increased 14C-2-deoxyglucose uptake into fat depots of fed rats and, surprisingly, free fatty acid (FFA) uptake into fat depots was elevated approximately twofold. The increased glucose and FFA uptake into adipose tissue was coupled with increased adipose tissue lipogenesis. Finally, olanzapine lowered fasting plasma FFA, and as it had no effect on isoproterenol-stimulated rises in plasma glucose, it blunted isoproterenol-stimulated in vivo lipolysis in fed rats. Collectively, these results suggest that olanzapine exerts several metabolic effects that together favor increased accumulation of fuel into adipose tissue, thereby increasing adiposity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ananth J, Parameswaran S, Gunatilake S . Side effects of atypical antipsychotic drugs. Curr Pharm Des 2004; 10: 2219–2229.
Ebenbichler CF, Laimer M, Eder U, Mangweth B, Weiss E, Hofer A et al. Olanzapine induces insulin resistance: results from a prospective study. J Clin Psychiatry 2003; 64: 1436–1439.
Haupt DW, Newcomer JW . Hyperglycemia and antipsychotic medications. J Clin Psychiatry 2001; 62 (Suppl 27): 15–26; discussion 40–41.
Newcomer JW . Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J Clin Psychiatry 2004; 65 (Suppl 18): 36–46.
Newcomer JW . Metabolic risk during antipsychotic treatment. Clin Ther 2004; 26: 1936–1946.
Newcomer JW . Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19 (Suppl 1): 1–93.
Fertig MK, Brooks VG, Shelton PS, English CW . Hyperglycemia associated with olanzapine. J Clin Psychiatry 1998; 59: 687–689.
Avella J, Wetli CV, Wilson JC, Katz M, Hahn T . Fatal olanzapine-induced hyperglycemic ketoacidosis. Am J Forensic Med Pathol 2004; 25: 172–175.
Torrey EF, Swalwell CI . Fatal olanzapine-induced ketoacidosis. Am J Psychiatry 2003; 160: 2241.
Newcomer JW . Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry 2007; 68 (Suppl 1): 20–27.
Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R et al. Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers. Neuropsychopharmacology 2008; 33: 1633–1641.
Kaddurah-Daouk R, McEvoy J, Baillie RA, Lee D, Yao JK, Doraiswamy PM et al. Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Mol Psychiatry 2007; 12: 934–945.
Vidarsdottir S, de Leeuw van Weenen JE, Frolich M, Roelfsema F, Romijn JA, Pijl H . Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab 2010; 95: 118–125.
Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B et al. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity 2006; 14: 36–51.
Arjona AA, Zhang SX, Adamson B, Wurtman RJ . An animal model of antipsychotic-induced weight gain. Behav Brain Res 2004; 152: 121–127.
Cooper GD, Pickavance LC, Wilding JP, Halford JC, Goudie AJ . A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology (Berl) 2005; 181: 80–89.
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.
Lee MD, Clifton PG . Meal patterns of free feeding rats treated with clozapine, olanzapine, or haloperidol. Pharmacol Biochem Behav 2002; 71: 147–154.
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.
Hartfield AW, Moore NA, Clifton PG . Effects of clozapine, olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat. Psychopharmacology (Berl) 2003; 167: 115–122.
Benvenga MJ, Leander JD . Increased food consumption by clozapine, but not by olanzapine, in satiated rats. Drug Dev Res 1997; 41: 48–50.
Minet-Ringuet J, Even PC, Goubern M, Tome D, Beaurepaire RD . Long term treatment with olanzapine mixed with the food in male rats induces body fat deposition with no increase in body weight and no thermogenic alteration. Appetite 2006; 46: 254–262.
Cooper GD, Pickavance LC, Wilding JP, Harrold JA, Halford JC, Goudie AJ . Effects of olanzapine in male rats: enhanced adiposity in the absence of hyperphagia, weight gain or metabolic abnormalities. J Psychopharmacol 2007; 21: 405–413.
Ader M, Kim SP, Catalano KJ, Ionut V, Hucking K, Richey JM et al. Metabolic dysregulation with atypical antipsychotics occurs in the absence of underlying disease: a placebo-controlled study of olanzapine and risperidone in dogs. Diabetes 2005; 54: 862–871.
Shearer J, Coenen KR, Pencek RR, Swift LL, Wasserman DH, Rottman JN . Long chain fatty acid uptake in vivo: comparison of [125I]-BMIPP and [3H]-bromopalmitate. Lipids 2008; 43: 703–711.
Robinson AM, Girard JR, Williamson DH . Evidence for a role of insulin in the regulation of lipogenesis in lactating rat mammary gland. Measurements of lipogenesis in vivo and plasma hormone concentrations in response to starvation and refeeding. Biochem J 1978; 176: 343–346.
Hajra AK . On extraction of acyl and alkyl dihydroxyacetone phosphate from incubation mixtures. Lipids 1974; 9: 502–505.
Bligh EG, Dyer WJ . A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959; 37: 911–917.
Ivy JL, Cortez MY, Chandler RM, Byrne HK, Miller RH . Effects of pyruvate on the metabolism and insulin resistance of obese Zucker rats. Am J Clin Nutr 1994; 59: 331–337.
Bergman RN, Hope ID, Yang YJ, Watanabe RM, Meador MA, Youn JH et al. Assessment of insulin sensitivity in vivo: a critical review. Diabetes Metab Rev 1989; 5: 411–429.
Crist GH, Xu B, Lanoue KF, Lang CH . Tissue-specific effects of in vivo adenosine receptor blockade on glucose uptake in Zucker rats. FASEB J 1998; 12: 1301–1308.
Lang CH, Dobrescu C, Meszaros K . Insulin-mediated glucose uptake by individual tissues during sepsis. Metab: Clin Exp 1990; 39: 1096–1107.
Fell MJ, Anjum N, Dickinson K, Marshall KM, Peltola LM, Vickers S et al. The distinct effects of subchronic antipsychotic drug treatment on macronutrient selection, body weight, adiposity, and metabolism in female rats. Psychopharmacology (Berl) 2007; 194: 221–231.
Caro J, Sinha M, Dohm G, California Uo . Insulin resistance in obesity. In: Bray G, Ricquier D, Spiegelman B (eds). UCLA Symposia on Molecular and Cellular Biology. Wiley-Liss: Keystone, Co, 1989, pp 203–218.
Chintoh AF, Mann SW, Lam L, Giacca A, Fletcher P, Nobrega J et al. Insulin resistance and secretion in vivo: effects of different antipsychotics in an animal model. Schizophr Res 2009; 108: 127–133.
Houseknecht KL, Robertson AS, Zavadoski W, Gibbs EM, Johnson DE, Rollema H . Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology 2007; 32: 289–297.
Haupt DW, Luber A, Maeda J, Melson AK, Schweiger JA, Newcomer JW . Plasma leptin and adiposity during antipsychotic treatment of schizophrenia. Neuropsychopharmacology 2005; 30: 184–191.
Acheson KJ, Schutz Y, Bessard T, Ravussin E, Jequier E, Flatt JP . Nutritional influences on lipogenesis and thermogenesis after a carbohydrate meal. Am J Physiol 1984; 246 (1 Pt 1): E62–E70.
Chwalibog A, Thorbek G . Energy expenditure by de novo lipogenesis. Br J Nutr 2001; 86: 309.
Acheson KJ, Schutz Y, Bessard T, Anantharaman K, Flatt JP, Jequier E . Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. Am J Clin Nutr 1988; 48: 240–247.
Jensen MD, Johnson CM . Contribution of leg and splanchnic free fatty acid (FFA) kinetics to postabsorptive FFA flux in men and women. Metabolism 1996; 45: 662–666.
Nelson RH, Basu R, Johnson CM, Rizza RA, Miles JM . Splanchnic spillover of extracellular lipase-generated fatty acids in overweight and obese humans. Diabetes 2007; 56: 2878–2884.
Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD . Splanchnic lipolysis in human obesity. J Clin Invest 2004; 113: 1582–1588.
Minet-Ringuet J, Even PC, Valet P, Carpene C, Visentin V, Prevot D et al. Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Mol Psychiatry 2007; 12: 562–571.
Luiken JJ, Dyck DJ, Han XX, Tandon NN, Arumugam Y, Glatz JF et al. Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane. Am J Physiol Endocrinol Metab 2002; 282: E491–E495.
Hucking K, Hamilton-Wessler M, Ellmerer M, Bergman RN . Burst-like control of lipolysis by the sympathetic nervous system in vivo. J Clin Invest 2003; 111: 257–264.
Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996; 14: 87–96.
Acknowledgements
The expert technical assistance of Beth Halle Gern, Stephanie Goshorn, Jamie G Spicer, and Ali Nairizi is greatly appreciated. VLA is the recipient of a Seed Grant from the American Medical Association, Foundation. JGJ was supported by an institutional NIDDK STEP-UP grant (R25 DK078381). This project was supported by NIH (DK062880) and the Pennsylvania Department of Health using Tobacco Settlement Funds. The Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Albaugh, V., Judson, J., She, P. et al. Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis. Mol Psychiatry 16, 569–581 (2011). https://doi.org/10.1038/mp.2010.33
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2010.33
Keywords
This article is cited by
-
HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor
Current Medical Science (2023)
-
Antipsychotics impair regulation of glucose metabolism by central glucose
Molecular Psychiatry (2022)
-
Gold nanoclusters eliminate obesity induced by antipsychotics
Scientific Reports (2022)
-
Disrupted sphingolipid metabolism following acute clozapine and olanzapine administration
Journal of Biomedical Science (2018)
-
May the Force Be With You: The Light and Dark Sides of the Microbiota–Gut–Brain Axis in Neuropsychiatry
CNS Drugs (2016)