Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Weight gain related to treatment with atypical antipsychotics is due to activation of PKC-β

The Pharmacogenomics Journal volume 10, pages 408–417 (2010)Cite this article

Abstract

Atypical antipsychotics (APDs) are currently used in clinical practice for a variety of mental disorders such as schizophrenia, bipolar disorder and severe behavioral disturbances. A well-known disadvantage of using these compounds is a propensity for weight gain, resulting frequently in obesity. The mechanisms underlying pharmacologically induced weight gain are still controversial. The objective of this study was to evaluate in vitro the effects of different APDs on adipogenic events in cultured human pre-adipocytes and in rat muscle-derived stem cells (MDSCs), aiming to identify a common intracellular event contributable to these drugs. Culture behavior was evaluated in terms of cell proliferation, lipid accumulation, gene expression and morphological features. Results indicate that APDs influence adipogenic events through changes in the differentiation and proliferation of pre-adipocytes and MDSCs that are brought on by protein kinase C-β (PKC-β) activation. These data identify a signaling route that could be a potential target of pharmacological approaches for preventing the weight gain associated with APD treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Hsiao JK . Effectiveness of antipsychotic drugs with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.

    Article  CAS  PubMed  Google Scholar 

  2. Jin H, Meyer JM, Mundaliar S, Jeste DV . Impact of atypical antipsychotic therapy on leptin, ghrelin and adiponectin. Schizophr Res 2008; 100: 70–85.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Borison R . Recent advances in the pharmacotherapy of schizophrenia. Harv Rev Psychiatry 1997; 4: 255–271.

    Article  CAS  PubMed  Google Scholar 

  4. Green M, Marshall B, Wirshing W, Ames D, Mintz J . Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 1997; 154: 799–804.

    Article  CAS  PubMed  Google Scholar 

  5. Lean ME, Pajonk FG . Patients on atypical antipsychotic drugs: another high-risk group for type 2 diabetes. Diabetes Care 2003; 26: 1597–1605.

    Article  CAS  PubMed  Google Scholar 

  6. Bellino S, Paradiso E, Bogetto F . Efficacy and tolerability of pharmacotherapies for borderline personality disorder. CNS Drugs 2008; 22: 671–692.

    Article  CAS  PubMed  Google Scholar 

  7. Roepke S, Merkl A, Dams A, Ziegenhorn A, Lammers CH . Preliminary evidence of improvement of depressive symptoms but not impulsivity in cluster B personality disorder patients treated with quetiapine: an open label trial. Pharmacopsychiatry 2008; 41: 176–181.

    Article  CAS  PubMed  Google Scholar 

  8. Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, Gebhardt N, Theisen FM . Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course. J Psychiatr Res 2009; 43: 620–626.

    Article  PubMed  Google Scholar 

  9. 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 2005; 30: 93–98.

    Article  PubMed  Google Scholar 

  10. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH . Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci USA 2007; 104: 3456–3459.

    Article  CAS  PubMed  Google Scholar 

  11. Hemmrich K, Gummersbach C, Pallua N, Luckhaus C, Fehsel K . Clozapine enhances differentiation of adipocyte progenitor cells. Mol Psychiatry 2006; 11: 980–983.

    Article  CAS  PubMed  Google Scholar 

  12. Yang LH, Chen TM, Yu ST, Chen YH . Olanzapine induces SREBP-1-related adipogenesis in 3T3-L1 cells. Pharmacol Res 2007; 56: 202–208.

    Article  CAS  PubMed  Google Scholar 

  13. Minet-Ringuet J, Even PC, Valet P, Carpéné C, de Beauurepaire R . Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Mol Psychiatry 2007; 12: 562–571.

    Article  CAS  PubMed  Google Scholar 

  14. Aguiari P, Leo S, Zavan B, Vindigni V, Rizzuto R . High glucose induces adipogenic differentiation of muscle-derived stem cells. Proc Natl Acad Sci USA 2008; 105: 1226–1231.

    Article  CAS  PubMed  Google Scholar 

  15. Brini M, De Giorgi F, Murgia M, Marsault R, Pozzan T . Subcellular analysis of Ca2+ homeostasis in primary cultures of skeletal muscle myotubes. Mol Biol Cell 1997; 8: 129–143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Denizot F, Lang R . Rapid colorimetric assay for cell growth and survival. J Immunol Methods 1986; 89: 271–277.

    Article  CAS  PubMed  Google Scholar 

  17. Ramirez-Zacarias JL, Castro-Munozledo F, Kuri-Harcuch W . Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with oil red O. Histochemistry 1992; 97: 493–497.

    Article  CAS  PubMed  Google Scholar 

  18. Xu Y, Mirmalek-Sani SH, Lin F, Zhang J, Oreffo RO . Adipocyte differentiation induced using nonspecific siRNA controls in cultured human mesenchymal stem cells. RNA 2007; 13: 1179–1183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Birkás Kováts D, Palik E, Faludi G, Cseh K . Possible connection between ghrelin, resistin and TNF-alpha levels and the metabolic syndrome caused by atypical antipsychotics. Neuropsychopharmacol Hung 2005; 7: 132–139.

    PubMed  Google Scholar 

  20. Gorobets LN . Weight gain in patients with schizophrenia and schizoaffective disorder induced by the long-term treatment with atypical antipsychotics. Zh Nevrol Psikhiatr Im SS Korsakova 2008; 108: 52–56.

    CAS  Google Scholar 

  21. Esen-Danaci A, Sarandöl A, Taneli F, Yurtsever F, Ozlen N . Effects of second generation antipsychotics on leptin and ghrelin. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1434–1438.

    Article  CAS  PubMed  Google Scholar 

  22. Kolotkin RL, Corey-Lisle PK, Crosby RD, Kan HJ, McQuade RD . Changes in weight and weight-related quality of life in a multicentre, randomized trial of aripiprazole versus standard care. Eur Psychiatry 2008; 23: 561–566.

    Article  PubMed  Google Scholar 

  23. Khazaal Y, Chatton A, Claeys F, Ribordy F, Zullino D, Cabanac M . Antipsychotic drug and body weight set-point. Physiol Behav 2008; 95: 157–160.

    Article  CAS  PubMed  Google Scholar 

  24. Musil R, Spellmann I, Riedel M, Dehning S, Bondy B . SNAP-25 gene polymorphisms and weight gain in schizophrenic patients. J Psychiatr Res 2008; 42: 863–970.

    Article  Google Scholar 

  25. Le Hellard S, Theisen FM, Haberhausen M, Raeder MB, Steen VM . Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related adverse effects? Mol Psychiatry 2009; 14: 308–317.

    Article  CAS  PubMed  Google Scholar 

  26. Albert SG, Grossberg GT, Thaipisuttikul PJ, Scouby J, Green E . Atypical antipsychotics and the risk of diabetes in an elderly population in long-term care: a retrospective nursing home chart review study. J Am Med Dir Assoc 2009; 10: 115–119.

    Article  PubMed  Google Scholar 

  27. Gregoor JG, van der Weide J, Mulder H, Cohen D, Heerdink ER . Polymorphism of the LEP-and LEPR gene and obesity in patients using antipsychotic medication. J Clin Psychopharmacol 2009; 29: 21–25.

    Article  CAS  PubMed  Google Scholar 

  28. Seo HJ, Jung YE, Woo YS, Jun TY, Chae JH, Bahk WM . Effect of augmented atypical antipsychotics on weight change in patients with major depressive disorder in a naturalistic setting. Hum Psychopharmacol 2009; 24: 135–143.

    Article  PubMed  Google Scholar 

  29. De Hert M, Schreurs V, Vancampfort D, Van Winkel R . Metabolic syndrome in people with schizophrenia: a review. World Psychiatry 2009; 8: 15–22.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Perkins DO . Predictors of non compliance in patients with schizophrenia. J Clin Psychiatry 2002; 63: 1121–1128.

    Article  PubMed  Google Scholar 

  31. Perkins DO, Johnson JL, Hamer RM, Zipursky RB, Lieberman JA . Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode. Schizophr Res 2006; 83: 53–63.

    Article  PubMed  Google Scholar 

  32. Weiden PJ, Mackell JA, McDonnell DD . Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res 2004; 66: 51–57.

    Article  PubMed  Google Scholar 

  33. Lexell J . Human aging, muscle mass, and fiber type composition. J Gerontol A Biol Sci Med Sci 1995; 50 (Spec No): 11–16.

    PubMed  Google Scholar 

  34. Guillet-Deniau I, Pichard AL, Koné A, Esnous C, Prip-Buus C . Glucose induces de novo lipogenesis in rat muscle satellite cells through a sterol-regulatory-element-binding-protein-1c-dependent pathway. J Cell Sci 2004; 117: 1937–1944.

    Article  CAS  PubMed  Google Scholar 

  35. Pinton P, Rimessi A, Marchi S, Orsini F, Rizzuto R . Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science 2007; 315: 659–663.

    Article  CAS  Google Scholar 

  36. Avignon A, Sultan A . PKC-B inhibition: a new therapeutic approach for diabetic complications? Diabetes Metab 2006; 32: 205–213.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by FIRB grant and local funds from the University of Padova to Roberta Cortivo and by AIRC, UMDF, PRRIITT, FISM, Telethon (GGP09128) and local funds from the University of Ferrara to Paolo Pinton.

Author information

Authors and Affiliations

  1. Psychiatric Clinic, University of Padova, Padova, Italy

    C Pavan

  2. Unit of Plastic and Reconstructive Surgery, University of Padova, Padova, Italy

    V Vindigni

  3. Department of Histology, Microbiology and Medical Biotechnology, University of Padova, Padova, Italy

    L Michelotto, G Abatangelo, R Cortivo & B Zavan

  4. Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI) and Emilia Romagna Laboratory BioPharmaNet, University of Ferrara, Ferrara, Italy

    A Rimessi & P Pinton

Authors
  1. C Pavan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V Vindigni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Michelotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Rimessi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Abatangelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Cortivo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Pinton
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Zavan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Zavan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pavan, C., Vindigni, V., Michelotto, L. et al. Weight gain related to treatment with atypical antipsychotics is due to activation of PKC-β. Pharmacogenomics J 10, 408–417 (2010). https://doi.org/10.1038/tpj.2009.67

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2009.67

Keywords

This article is cited by

Search

Advanced search

Quick links