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Clozapine enhances differentiation of adipocyte progenitor cells

Molecular Psychiatry volume 11, pages 980–981 (2006)Cite this article

A common side effect of antipsychotic treatment with atypical neuroleptics is a significant weight gain. This stabilizes in the short to medium term but with clozapine often continues beyond the first year leading to weight gains of up to 20–30 kg.1 This increase in weight is significantly correlated with clinical improvements, but the causes of treatment-emergent weight gain in schizophrenic patients are currently unknown. It is assumed that the perception of satiety is impaired, as patients experience a lower suppression of appetite after meals when consuming atypical neuroleptics.1 Supporting this hypothesis, clozapine has been found to increase serum leptin levels within days after starting treatment.2 Unfortunately, strict food reduction shows little success indicating that central pathways rather than peripheral actions of atypical neuroleptics or their mediators are involved in weight gain. Evaluation of the body composition revealed an increase in body fat under antipsychotic treatment with atypical antipsychotic drugs,3 and blockade of serotonin and histamine receptors by these drugs was previously shown to be associated with weight gain.4 In addition to enhanced lipid accumulation in adipocytes, enhanced differentiation of preadipocytes can increase body fat. Our study addresses the question of whether clozapine-induced weight gain is based on neo-formation of adipose tissue from precursor cells. All experiments had been approved by the Ethical Committee of the Aachen University of Technology.

Preadipocytes were isolated from human abdominal subcutaneous adipose tissue samples (n=7) and cultured in Dulbecco's modified Eagle's medium (DMEM)/Ham's F12 (F12) until confluence.5 Adipogenic conversion was then promoted for 14 days by changing medium to fetal calf serum-free DMEM/F12, supplemented with 66 nM insulin, 100 nM dexamethasone, 0.5 mM isobutylmethylxanthine (IBMX), 0.1 μg ml−1 pioglitazone, 1 nM triiodo-L-thyronine and 10 μg ml−1 human transferrin. After 5 days of incubation, medium was used as described before but without IBMX and pioglitazone for 9 more days. Clozapine (5–50 μ M) was added for the first 5 days during differentiation. The mood-stabilizing drug lithium chloride (2 mM) was used as negative control. Cells were counted and fluorescence microscopy was applied to detect apoptotic cells stained for 5 min by Hoechst 33342 (8 μg/ml). To evaluate preadipocyte differentiation on the molecular level, the activity of glycerol 3-phosphate dehydrogenase (GPDH), a molecular key marker of adipogenic conversion, was determined after 14 days by measuring enzyme activity5 and normalizing for protein content and cell number. To confirm adipocyte maturation from progenitor cells morphologically, Oil Red O staining was applied.

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Acknowledgements

This project has been supported by a grant from the Interdisciplinary Centre for Clinical Research ‘Biomat’ within the Faculty of Medicine at the RWTH Aachen University (IZKF VVB110-c).

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Authors and Affiliations

  1. Department of Plastic Surgery and Hand Surgery–Burn Centre, University Hospital of the RWTH Aachen University, Aachen, Germany

    K Hemmrich, C Gummersbach & N Pallua

  2. Interdisciplinary Centre for Clinical Research ‘BIOMAT.’, University Hospital of the Aachen University of Technology, Aachen, Germany

    K Hemmrich & C Gummersbach

  3. Department of Psychiatry, Neurobiochemical Research Unit, Heinrich-Heine-University of Duesseldorf, Düsseldorf, Germany

    C Luckhaus & K Fehsel

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  1. K Hemmrich
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Correspondence to K Fehsel.

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Hemmrich, K., Gummersbach, C., Pallua, N. et al. Clozapine enhances differentiation of adipocyte progenitor cells. Mol Psychiatry 11, 980–981 (2006). https://doi.org/10.1038/sj.mp.4001892

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