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Animal Models

Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice

International Journal of Obesity volume 39, pages 1339–1348 (2015)Cite this article

Subjects

Abstract

Background:

Maternal obesity increases offspring propensity to metabolic dysfunctions and to non-alcoholic fatty liver disease (NAFLD), which may lead to cirrhosis or liver cancer. The circadian clock is a transcriptional/epigenetic molecular machinery synchronising physiological processes to coordinate energy utilisation within a 24-h light/dark period. Alterations in rhythmicity have profound effects on metabolic pathways, which we sought to investigate in offspring with programmed NAFLD.

Methods:

Mice were fed a standard or an obesogenic diet (OD), before and throughout pregnancy, and during lactation. Offspring were weaned onto standard or an OD at 3 weeks postpartum and housed in 12:12 light/dark conditions. Biochemical and histological indicators of NAFLD and fibrosis, analysis of canonical clock genes with methylation status and locomotor activity were investigated at 6 months.

Results:

We show that maternal obesity interacts with an obesogenic post-weaning diet to promote the development of NAFLD with disruption of canonical metabolic rhythmicity gene expression in the liver. We demonstrate hypermethylation of BMAL-1 (brain and muscle Arnt like-1) and Per2 promoter regions and altered 24-h rhythmicity of hepatic pro-inflammatory and fibrogenic mediators.

Conclusions:

These data implicate disordered circadian rhythms in NAFLD and suggest that disruption of this system during critical developmental periods may be responsible for the onset of chronic liver disease in adulthood.

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Acknowledgements

We thank Jahm Persaud, Department of Clinical Biochemistry Royal Free Hospital, UCLH/UCL Comprehensive Biomedical Research Centre, for his invaluable help. We also thank Joaquim Pombo and Paul Seed, Women’s Health Academic Centre, King’s College London, for technical assistance. This study was supported by Wellcome Trust and Fiorina Elliot Fellowship to JAO and My First AIRC Grant to MV (n.13419).

Author information

Authors and Affiliations

  1. Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK

    A Mouralidarane, J Soeda, R Carter, S Ray, P Cordero, M Vinciguerra & J A Oben

  2. Women’s Health Academic Centre, King’s College London, St Thomas’ Hospital, London, UK

    A Mouralidarane, D Sugden, A Bocianowska, L Poston & P D Taylor

  3. Histopathology Department, University College Hospital, University College London, London, UK

    R Saraswati & M Novelli

  4. Department of Liver Medicine and Transplant, Sheila Sherlock Liver Centre, University College London, Royal Free Hospital, London, UK

    G Fusai

  5. Gastroenterology Unit, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy

    M Vinciguerra

  6. School of Science and Technology, Nottingham Trent University, Nottingham, UK

    M Vinciguerra

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  1. A Mouralidarane
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  2. J Soeda
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  9. M Novelli
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Corresponding author

Correspondence to M Vinciguerra.

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Mouralidarane, A., Soeda, J., Sugden, D. et al. Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice. Int J Obes 39, 1339–1348 (2015). https://doi.org/10.1038/ijo.2015.85

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