Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis
V L Albaugh, J G Judson, P She, C H Lang, K P Maresca, J L Joyal, C J Lynch, V L Albaugh, J G Judson, P She, C H Lang, K P Maresca, J L Joyal, C J Lynch
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 (14)C-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 (14)C-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.
Conflict of interest statement
Conflict of Interest: The authors declare no conflicts of interest.
Figures
References
- Ananth J, Parameswaran S, Gunatilake S. Side effects of atypical antipsychotic drugs. Curr Pharm Des. 2004;10(18):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 Dec;64(12):1436–1439.
- Haupt DW, Newcomer JW. yperglycemia and antipsychotic medications. J Clin Psychiatry. 2001;62(27):15–26. discussion 40-11.
- Newcomer JW. Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J Clin Psychiatry. 2004;65(18):36–46.
- Newcomer JW. Metabolic risk during antipsychotic treatment. Clinical therapeutics. 2004 Dec;26(12):1936–1946.
- Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS drugs. 2005;19(1):1–93.
- Fertig MK, Brooks VG, Shelton PS, English CW. Hyperglycemia associated with olanzapine. J Clin Psychiatry. 1998 Dec;59(12):687–689.
- Avella J, Wetli CV, Wilson JC, Katz M, Hahn T. Fatal olanzapine-induced hyperglycemic ketoacidosis. Am J Forensic Med Pathol. 2004 Jun;25(2):172–175.
- Torrey EF, Swalwell CI. Fatal olanzapine-induced ketoacidosis. Am J Psychiatry. 2003 Dec;160(12):2241.
- Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007;68(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 Jun;33(7):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 Oct;12(10):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 Jan;95(1):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 Jan;14(1):36–51.
- Arjona AA, Zhang SX, Adamson B, Wurtman RJ. An animal model of antipsychotic-induced weight gain. Behav Brain Res. 2004 Jun 4;152(1):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 Aug;181(1):80–89.
- Goudie AJ, Smith JA, Halford JC. Characterization of olanzapine-induced weight gain in rats. J Psychopharmacol. 2002 Dec;16(4):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 Apr;75(1):133–140.
- Lee MD, Clifton PG. Meal patterns of free feeding rats treated with clozapine, olanzapine, or haloperidol. Pharmacol Biochem Behav. 2002 Jan-Feb;71(1-2):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 Mar;16(1):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 May;167(2):115–122.
- Benvenga MJ, Leander, JD Increased food consumption by clozapine, but not by olanzapine, in satiated rats. Drug Development Research. 1997;41(1):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 Mar 18;46(3):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 Jun;21(4):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 Mar;54(3):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 Aug;43(8):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 Oct 15;176(1):343–346.
- Hajra AK. On extraction of acyl and alkyl dihydroxyacetone phosphate from incubation mixtures. Lipids. 1974 Aug;9(8):502–505.
- Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):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 Feb;59(2):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/metabolism reviews. 1989 Aug;5(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 Oct;12(13):1301–1308.
- Lang CH, Dobrescu C, Meszaros K. Insulin-mediated glucose uptake by individual tissues during sepsis. Metabolism: clinical and experimental. 1990 Oct;39(10):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 Oct;194(2):221–231.
- Caro J, Sinha M, Dohm G. California Uo Insulin Resistance in Obesity. In: Bray G, Ricquier D, Spiegelman B, editors. 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. Schizophrenia research. 2009 Mar;108(1-3):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 Oct 11;32(2):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 Jan;30(1):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 Jan;246(1 Pt 1):E62–70.
- Chwalibog A, Thorbek G. Energy expenditure by de novo lipogenesis. Br J Nutr. 2001 Aug;86(2):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 Aug;48(2):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 May;45(5):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 Dec;56(12):2878–2884.
- Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. J Clin Invest. 2004 Jun;113(11):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 Jun;12(6):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 Feb;282(2):E491–495.
- 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 Jan;111(2):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 Feb;14(2):87–96.
Source: PubMed