Long-term administration of olanzapine induces adiposity and increases hepatic fatty acid desaturation protein in female C57BL/6J mice

Document Type : Original Article

Authors

1 Department of Veterinary Medicine, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan

2 Department of Psychiatry, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Taichung 40705, Taiwan

3 Department of Social Work and Child Welfare, Providence University, 200, Sec. 7, Taiwan Boulevard, Taichung 43301, Taiwan

4 Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan

Abstract

Objective(s): Weight gain and metabolic disturbances such as dyslipidemia, are frequent side effects of second-generation antipsychotics, including olanzapine. This study examined the metabolic effects of chronic olanzapine exposure. In addition, we investigated the hepatic fatty acid effects of olanzapine in female C57BL/6J mice fed a normal diet.
Materials and Methods: Female C57BL/6J mice orally received olanzapine or normal saline for 7 weeks. The effects of long-term olanzapine exposure on body weight changes, food efficiency, blood glucose, triglyceride (TG), insulin, and leptin levels were observed. Hepatic TG and abdominal fat mass were investigated, and fat cell morphology was analyzed through histopathological methods. The levels of protein markers of fatty acid regulation in the liver, namely fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD-1), were measured.
Results: Olanzapine treatment increased the food intake of the mice as well as their body weight. Biochemical analyses showed that olanzapine increased blood TG, insulin, leptin, and hepatic TG. The olanzapine group exhibited increased abdominal fat mass and fat cell enlargement in abdominal fat tissue. Western blotting of the mouse liver revealed significantly higher (1.6-fold) levels of SCD-1 in the olanzapine group relative to the control group; by contrast, FAS levels in the two groups did not differ significantly.
Conclusion: Enhanced lipogenesis triggered by increased hepatic SCD-1 activity might be a probable peripheral mechanism of olanzapine-induced dyslipidemia. Some adverse metabolic effects of olanzapine may be related to the disturbance of lipid homeostasis in the liver.

Keywords

Main Subjects

References

1. de Leon J, Susce MT, Johnson M, Hardin M, Pointer L, Ruano G, et al. A clinical study of the association of antipsychotics with hyperlipidemia. Schizophr Res 2007;92:95-102.
2. Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, Gebhardt N, Remschmidt H, Krieg JC, et al. Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course. J Psychiatr Res 2009;43:620-626.
3. Rzewuska M. Metabolic risk during antipsychotic treatment in patients with schizophrenia. Psychiatr Pol 2007;41:457-472.
4. 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.
5. Kluge M, Schuld A, Himmerich H, Dalal M, Schacht A, Wehmeier PM, et al. Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study. J Clin Psychopharmacol 2007;27:662-626.
6. McEvoy JP, Meyer JM, Goff DC, Nasrallah HA, Davis SM, Sullivan L, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005;80:19-32.
7. Meyer JM, Nasrallah HA, McEvoy JP, Goff DC, Davis SM, Chakos M, et al. The Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical comparison of subgroups with and without the metabolic syndrome. Schizophr Res 2005;80:9-18.
8. Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res 2010;123:225-233.
9. Haro JM, Novick D, Suarez D, Roca M. Antipsychotic treatment discontinuation in previously untreated patients with schizophrenia: 36-month results from the SOHO study. J Psychiatr Res 2009;43:265-273.
10. Kurzthaler I, Fleischhacker WW. The clinical implications of weight gain in schizophrenia. J Clin Psychiatry 2001;62 Suppl 7:32-37.
11. Tighe S, Dinan T. An overview of the central control of weight regulation and the effect of antipsychotic medication. J Clin Psychopharmacol 2005;19:36-46.
12. Attie AD, Krauss RM, Gray-Keller MP, Brownlie A, Miyazaki M, Kastelein JJ, et al. Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia. J Lipid Res 2002;43:1899-1907.
13. Miyazaki M, Kim YC, Gray-Keller MP, Attie AD, Ntambi JM. The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1. J Biol Chem 2000;275:30132-30138.
14. Issandou M, Bouillot A, Brusq JM, Forest MC, Grillot D, Guillard R, et al. Pharmacological inhibition of stearoyl-CoA desaturase 1 improves insulin sensitivity in insulin-resistant rat models. Eur J Pharmacol 2009;618:28-36.
15. Flowers MT, Ntambi JM. Stearoyl-CoA desaturase and its relation to high-carbohydrate diets and obesity. Biochim Biophys Acta 2009;1791:85-91.
16. Paillard F, Catheline D, Duff FL, Bouriel M, Deugnier Y, Pouchard M, et al. Plasma palmitoleic acid, a product of stearoyl-coA desaturase activity, is an independent marker of triglyceridemia and abdominal adiposity. Nutr Metab Cardiovasc Dis 2008;18:436-440.
17. Polymeropoulos MH, Licamele L, Volpi S, Mack K, Mitkus SN, Carstea ED, et al. Common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol supports a key role of lipid homeostasis in schizophrenia. Schizophr Res 2009;108:134-142.
18. Lauressergues E, Staels B, Valeille K, Majd Z, Hum DW, Duriez P, et al. Antipsychotic drug action on SREBPs-related lipogenesis and cholesterogenesis in primary rat hepatocytes. Naunyn Schmiedebergs Arch Pharmacol 2010;381:427-439.
19. Ferno J, Raeder MB, Vik-Mo AO, Skrede S, Glambek M, Tronstad KJ, et al. Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action? Pharmacogenomics J 2005;5:298-304.
20. Vik-Mo AO, Birkenaes AB, Ferno J, Jonsdottir H, Andreassen OA, Steen VM. Increased expression of lipid biosynthesis genes in peripheral blood cells of olanzapine-treated patients. Int J
Neuropsychopharmacol 2008;11:679-684.
21. Ferno J, Vik-Mo AO, Jassim G, Havik B, Berge K, Skrede S, et al. Acute clozapine exposure in vivo induces lipid accumulation and marked sequential changes in the expression of SREBP, PPAR, and LXR target genes in rat liver. Psychopharmacology 2009;203:73-84.
22. Coccurello R, Brina D, Caprioli A, Conti R, Ghirardi O, Schepis F, et al. 30 days of continuous olanzapine infusion determines energy imbalance, glucose intolerance, insulin resistance, and dyslipidemia in mice. J Clin Psychopharmacol 2009;29:576-583.
23. Shertzer HG, Kendig EL, Nasrallah HA, Johansson E, Genter MB. Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen and tetrahydroindenoindole. Int J Obes 2010;34:970-979.
24. Yoon S, Noh JS, Choi SY, Baik JH. Effects of atypical antipsychotic drugs on body weight and food intake in dopamine D2 receptor knockout mice. Biochem Biophys Res Commun 2010;393:235-241.
25. Schmidt RH, Jokinen JD, Massey VL, Falkner KC, Shi X, Yin X, et al. Olanzapine activates hepatic mammalian target of rapamycin: new mechanistic insight into metabolic dysregulation with atypical antipsychotic drugs. J Pharmacol Exp Ther 2013;347:126-135.
26. Spisni E, Tugnoli M, Ponticelli A, Mordenti T, Tomasi V. Hepatic steatosis in artificially fed marine teleosts. J Fish Dis 1998; 21:177-184.
27. Chang GR, Wu YY, Chiu YS, Chen WY, Liao JW, Hsu HM, et al. Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice. Basic Clin Pharmacol Toxicol 2009; 105:188-198.
28. Chang GR, Chen PL, Hou PH, Mao FC. Resveratrol protects against diet-induced atherosclerosis by reducing low-density lipoprotein cholesterol and inhibiting inflammation in apolipoprotein E-deficient mice. Iran J Basic Med Sci 2015 ;18:1063-1071.
29. Chang GR, Chiu YS, Wu YY, Chen WY, Liao JW, Chao TH, et al. Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice. J Pharmacol Sci 2009;109: 496-503.
30. Chang GR, Chiu YS, Wu YY, Lin YC, Hou PH, Mao FC1. Rapamycin impairs HPD-induced beneficial effects on glucose homeostasis. Br J Pharmacol 2015; 172: 3793-3804.
31. Arjona AA, Zhang SX, Adamson B, Wurtman RJ. An animal model of antipsychotic-induced weight gain. Behav Brain Res 2004;152:121-127.
32. Cope MB, Nagy TR, Fernandez JR, Geary N, Casey DE, Allison DB. Antipsychotic drug-induced weight gain: development of an animal model. Int J Obes. 2005;29:607-614.
33. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008;13:27-35.
34. Kirk SL, Glazebrook J, Grayson B, Neill JC, Reynolds GP. Olanzapine-induced weight gain in the rat: role of 5-HT2C and histamine H1 receptors. Psychopharmacology 2009;207:119-125.
35. Weston-Green K, Huang XF, Lian J, Deng C. Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels. Eur Neuropsychopharmacol 2012;22:364-373.
36. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. From the Cover: Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci U S A 2007;104:3456-3459.
37. Correll CU. Monitoring and management of antipsychotic-related metabolic and endocrine adverse events in pediatric patients. Int Rev Psychiatry 2008;20:195-201.
38. Esen-Danaci A, Sarandol A, Taneli F, Yurtsever F, Ozlen N. Effects of second generation antipsychotics on leptin and ghrelin. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1434-1438.
39. Zugno AI, Barcelos M, Oliveira L, Canever L, Luca RD, Fraga DB, et al. Energy metabolism, leptin, and biochemical parameters are altered in rats subjected to the chronic administration of olanzapine. Rev Bras Psiquiatr 2012;34:168-175.
40. Atmaca M, Kuloglu M, Tezcan E, Ustundag B. Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. J Clin Psychiatry 2003;64:598-604.
41. 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.
42. 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.
43. Graham KA, Perkins DO, Edwards LJ, Barrier RC, Jr., Lieberman JA, Harp JB. Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis. Am J Psychiatry 2005;162:118-123.
44. Oriot P, Feys JL, Mertens de Wilmars S, Misson A, Ayache L, Fagnart O, et al. Insulin sensitivity, adjusted beta-cell function and adiponectinaemia among lean drug-naive schizophrenic patients treated with atypical antipsychotic drugs: a nine-month prospective study. Diabetes Metab 2008;34:490-496.
45. Ryan MC, Flanagan S, Kinsella U, Keeling F, Thakore JH. The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophrenia. Life Sci 2004;74:1999-2008.
46. Fell MJ, Marshall KM, Williams J, Neill JC. Effects of the atypical antipsychotic olanzapine on reproductive function and weight gain in female rats. J Psychopharmacol 2004;18:149-155.
47. Chintoh AF, Mann SW, Lam TK, Giacca A, Remington G. Insulin resistance following continuous, chronic olanzapine treatment: an animal model. Schizophr Res 2008;104:23-30.
48. 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.
49. Victoriano M, de Beaurepaire R, Naour N, Guerre-Millo M, Quignard-Boulange A, Huneau JF, et al. Olanzapine-induced accumulation of adipose tissue is associated with an inflammatory state. Brain Res 2010;1350:167-175.
50. 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.
51. Kang SH, Lee JI. Metabolic disturbances independent of body mass in patients with schizophrenia taking atypical antipsychotics. Psychiatry Investig 2015;12:242-248.
52. Skrede S, Ferno J, Vazquez MJ, Fjaer S, Pavlin T, Lunder N, et al. Olanzapine, but not aripiprazole, weight-independently elevates serum triglycerides and activates lipogenic gene expression in female rats. Int J Neuropsychopharmacol 2012;15:163-179.
53. Birkenaes AB, Birkeland KI, Engh JA, Faerden A, Jonsdottir H, Ringen PA, et al. Dyslipidemia independent of body mass in antipsychotic-treated patients under real-life conditions. J Clin Psychopharmacol 2008;28:132-137.
54. Almeras N, Despres JP, Villeneuve J, Demers MF, Roy MA, Cadrin C, et al. Development of an atherogenic metabolic risk factor profile associated with the use of atypical antipsychotics. J Clin Psychiatry 2004;65:557-564.
55. 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 2007;32:765-72.
56. Cohen P, Ntambi JM, Friedman JM. Stearoyl-CoA desaturase-1 and the metabolic syndrome. Curr Drug Targets Immune Endocr Metabol Disord 2003;3:271-280.
57. Perez-Iglesias R, Vazquez-Barquero JL, Amado JA, Berja A, Garcia-Unzueta MT, Pelayo-Teran JM, et al. Effect of antipsychotics on peptides involved in energy balance in drug-naive psychotic patients after 1 year of treatment. J Clin Psychopharmacol 2008;28:289-295.
58. Wu RR, Zhao JP, Guo XF, He YQ, Fang MS, Guo WB, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. Am J Psychiatry 2008;165:352-358.
59. Chintoh AF, Mann SW, Lam L, Lam C, Cohn TA, Fletcher PJ, et al. Insulin resistance and decreased glucose-stimulated insulin secretion after acute olanzapine administration. J Clin Psychopharmacol 2008;28:494-499.
60. Chiu CC, Chen KP, Liu HC, Lu ML. The early effect of olanzapine and risperidone on insulin secretion in atypical-naive schizophrenic patients. J Clin Psychopharmacol 2006;26:504-7.
61. Weston-Green K, Huang XF, Deng C. Olanzapine treatment and metabolic dysfunction: a dose response study in female Sprague Dawley rats. Behav Brain Res 2011;217:337-346.
62. Spoelstra JA, Stolk RP, Cohen D, Klungel OH, Erkens JA, Leufkens HG, et al. Antipsychotic drugs may worsen metabolic control in type 2 diabetes mellitus. J Clin Psychiatry 2004;65:674-678.
63. van Winkel R, De Hert M, Wampers M, Van Eyck D, Hanssens L, Scheen A, et al. Major changes in glucose metabolism, including new-onset diabetes, within 3 months after initiation of or switch to atypical antipsychotic medication in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2008;69:472-429.
64. Chiu CC, Chen CH, Chen BY, Yu SH, Lu ML. The time-dependent change of insulin secretion in schizophrenic patients treated with olanzapine. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:866-870.
65. Smith RC, Lindenmayer JP, Davis JM, Kelly E, Viviano TF, Cornwell J, et al. Effects of olanzapine and risperidone on glucose metabolism and insulin sensitivity in chronic schizophrenic patients with long-term antipsychotic treatment: a randomized 5-month study. J Clin Psychiatry. 2009;70:1501-1513.
66. Newcomer JW, Ratner RE, Eriksson JW, Emsley R, Meulien D, Miller F, et al. A 24-week, multicenter, open-label, randomized study to compare changes in glucose metabolism in patients with schizophrenia receiving treatment with olanzapine, quetiapine, or risperidone. J Clin Psychiatry 2009;70:487-499.
67. Goff DC, Cather C, Evins AE, Henderson DC, Freudenreich O, Copeland PM, et al. Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. J Clin Psychiatry 2005;66:183-94; quiz 47, 273-274.
68. Liao CH, Chang CS, Wei WC, Chang SN, Liao CC, Lane HY, et al. Schizophrenia patients at higher risk of diabetes, hypertension and hyperlipidemia: a population-based study. Schizophr Res 2011;126:110-116.
69. Baptista T, Kin NM, Beaulieu S, de Baptista EA. Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives. Pharmacopsychiatry 2002;35:205-219.
70. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS drugs. 2005;19 Suppl 1:1-93.

Iranian Journal of Basic Medical Sciences
Volume 21, Issue 5
May 2018
Pages 495-501

Files

Share

How to cite

Statistics