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Overweight induced by chronic risperidone exposure is correlated with overexpression of the SREBP-1c and FAS genes in mouse liver

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Abstract

Weight gain and metabolic disturbances, such as dyslipidemia and hyperglycaemia, are common side effects of most antipsychotic drugs, including risperidone. The aim of this study was to investigate the effects of chronic treatment with risperidone on body weight, fat accumulation, liver weight, and hepatic expression of key genes involved in lipid metabolism in female mice. We also addressed the mechanism of risperidone induction of metabolic side effects by exploring its effect on lipid and cholesterol metabolism in primary cultures of rat hepatocytes. Eleven weeks of treatment with long-acting risperidone (12.5 mpk/week) resulted in a significant weight gain associated with an increase of liver and adipose tissue weight. These effects were positively correlated with hepatic mRNA induction of two key genes involved in lipogenesis: sterol regulatory element binding protein-1c (SREBP-1c) and fatty acid synthase (FAS). Furthermore, in line with these in vivo results, risperidone elicited significant inductions of SREBP-1 maturation and FAS mRNA expression in primary cultures of rat hepatocytes associated with an increase of free fatty acid, triacylglycerol, and phospholipid synthesis as assessed by acetate incorporation. The current investigations underscore the usefulness of a mouse model to study the weight gain observed with risperidone treatment in humans. This study shows that risperidone induces similar effects in the liver (in vivo) and in hepatocyte cell cultures (in vitro) on the expression of key genes and/or proteins that control lipid metabolism. This suggests that risperidone could alter lipid metabolism in the liver and induce weight gain in a way that is partly independent of its action on the central nervous system.

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Abbreviations

ACO:

Acyl-CoA oxidase

APD:

Antipsychotic drug

CE:

Cholesteryl esters

CPT1A:

Carnitine-palmitoyltransferase 1A

FAS:

Fatty acid synthase

FC:

Free cholesterol

FFA:

Free fatty acid

HMGCoAR:

3-Hydroxy-3-methylglutaryl-CoA reductase

HNE:

4-Hydroxy-2-nonenal

LDL-r:

Low-density lipoprotein receptor

LXRα:

Liver X receptor α

MDA:

Malondialdehyde

NF-κB:

Nuclear factor-kappa B

PPARα:

Peroxisome proliferator-activated receptor α

PPARγ:

Peroxisome proliferator-activated receptor γ

PRHC:

Primary rat hepatocyte cultures

SDS:

Sodium dodecyl sulfate

SREBP-1:

Sterol regulatory element-binding protein-1

SREBP-2:

Sterol regulatory element-binding protein-2

TNFα:

Tumor necrosis factor-α

TG:

Triacylglycerides

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Acknowledgments

This work was supported by Région Nord Pas de Calais France et le Fonds de Développement Européen Régional. We would thank Luc De Vries for critically reading the manuscript

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Authors and Affiliations

  1. University Lille Nord de France, Lille, France

    Françoise Martin, Audrey Helleboid, Régis Bordet, Gérald Luc, Bart Staels & Patrick Duriez

  2. Inserm UMR 1011, Lille, France

    Françoise Martin, Audrey Helleboid, Emmanuel Bouchaert, Gérald Luc & Bart Staels

  3. Pasteur Institute, Lille, France

    Françoise Martin, Audrey Helleboid, Gérald Luc & Bart Staels

  4. Faculty of Pharmacy, Institute of Predictive Medicine and Therapeutics Research, Lille, France

    Françoise Martin, Audrey Helleboid, Gérald Luc, Bart Staels & Patrick Duriez

  5. Department of Medical Pharmacology-EA 1046, Faculty of Medicine, Institute of Predictive Medicine and Therapeutics Research, Lille, France

    Régis Bordet & Patrick Duriez

  6. Department of Cellular and Molecular Biology, Pierre Fabre Research Center, 17 Avenue Jean Moulin, 81106, Castres, France

    Emilie Lauressergues & Didier Cussac

  7. Genfit SA, Loos, France

    Dean Hum & Zouher Majd

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  1. Emilie Lauressergues
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  2. Françoise Martin
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  3. Audrey Helleboid
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  4. Emmanuel Bouchaert
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  6. Régis Bordet
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  7. Dean Hum
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  8. Gérald Luc
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  9. Zouher Majd
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  10. Bart Staels
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  11. Patrick Duriez
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Correspondence to Emilie Lauressergues.

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Presented in alphabetical order because Emilie Lauressergues and Françoise Martin participated equally this work and should be considered as first co-authors.

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Lauressergues, E., Martin, F., Helleboid, A. et al. Overweight induced by chronic risperidone exposure is correlated with overexpression of the SREBP-1c and FAS genes in mouse liver. Naunyn-Schmied Arch Pharmacol 383, 423–436 (2011). https://doi.org/10.1007/s00210-010-0597-3

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  • DOI: https://doi.org/10.1007/s00210-010-0597-3

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