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Tricyclic antipsychotics promote adipogenic gene expression to potentiate preadipocyte differentiation in vitro

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Abstract

Antipsychotic-induced weight gain is a well-established but poorly understood clinical phenomenon. New mechanistic insights into how antipsychotics modulate adipose physiology are sorely needed, in hopes of either devising a therapeutic intervention to ameliorate weight gain or contributing to improved design of future agents. In this study, we have hypothesized that the weight gain-associated tricyclic antipsychotics clozapine and chlorpromazine directly impact adipose tissue by potentiating adipogenic differentiation of preadipocytes. Utilizing a well-established in vitro model system (3T3-L1 preadipocyte cell line), we demonstrate that, when applied specifically during induction of adipogenic differentiation, both clozapine and chlorpromazine significantly potentiate in vitro adipogenesis, observed as morphological changes and increased intracellular lipid accumulation. These persistent effects, observed at endpoints well after the end of antipsychotic exposure, are accompanied by increased transcript- and protein-level expression of the mature adipocyte marker perilipin-1, as indicated by RT-qPCR and Western blotting, but not by further upregulation of pro-adipogenic transcription factors versus positive controls. Our findings point to a possible physiological mechanism of antipsychotic-induced hyperplasia, with potentiated expression of mature adipocyte markers enhancing the differentiation and maturation of preadipocytes.

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Abbreviations

Clz:

Clozapine

Cpz:

Chlorpromazine

CEBP:

CCAAT-enhancer-binding protein

ORO:

Oil Red O

PPAR:

Peroxisome proliferator-activated receptor

Plpn-1:

Perilipin-1

PI:

Post-induction

RT-qPCR:

Reverse-transcription quantitative (real-time) PCR

UD:

Undifferentiated

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Acknowledgements

The authors thank Kurt Gibbs (Morehead State University) for advice regarding RT-qPCR assays, Amber Hall (formerly of Morehead State University) for contributions to RT-qPCR data collection, and Qin Wang (University of Alabama at Birmingham) for providing frozen 3T3-L1 stock.

Funding

This work was supported by the National Institutes of Health [grant number P20GM103436].

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Authors and Affiliations

  1. Department of Biology, University of North Alabama, UNA, One Harrison Plaza, Box 5048, Florence, AL, 35632, USA

    Christopher M. Cottingham

  2. Department of Biology and Chemistry, Morehead State University, 103 Lappin Hall, Morehead, KY, 40351, USA

    Taylor Patrick, Morgan A. Richards & Kirkland D. Blackburn

  3. University of Kentucky College of Medicine, UK Medical Center MN 150, Lexington, KY, 40536, USA

    Taylor Patrick

  4. School of Rehabilitation and Health Sciences, Ohio State University, 453 West 10th Avenue, Columbus, OH, 43210, USA

    Morgan A. Richards

  5. Kentucky College of Osteopathic Medicine, 147 Sycamore Street, Pikeville, KY, 41501, USA

    Kirkland D. Blackburn

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  1. Christopher M. Cottingham
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Correspondence to Christopher M. Cottingham.

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Cottingham, C.M., Patrick, T., Richards, M.A. et al. Tricyclic antipsychotics promote adipogenic gene expression to potentiate preadipocyte differentiation in vitro. Human Cell 33, 502–511 (2020). https://doi.org/10.1007/s13577-020-00372-4

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  • DOI: https://doi.org/10.1007/s13577-020-00372-4

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