Letter | Published:

Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring

Nature volume 467, pages 963966 (21 October 2010) | Download Citation

Abstract

The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic1,2. Having either parent obese is an independent risk factor for childhood obesity3. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established4, the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs β-cell ‘dysfunction’ in rat F1 female offspring. Chronic HFD consumption in Sprague–Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P < 0.01); genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed (P < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring.

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Gene Expression Omnibus

Data deposits

Gene expression data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo ) and are accessible using GEO series accession number GSE19877.

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Acknowledgements

This work is supported by the National Health and Medical Research Council (NHMRC) of Australia (M.J.M.). S.F.N. is supported by Ministry of Higher Education and National University of Malaysia, R.C.Y.L. is supported by the NHMRC Peter Doherty Fellowship.

Author information

Affiliations

  1. Department of Pharmacology, School of Medical Sciences, University of New South Wales, New South Wales, Sydney 2052, Australia

    • Sheau-Fang Ng
    •  & Margaret J. Morris
  2. Ramaciotti Centre for Gene Function Analysis and School of Biotechnology and Biomolecular Sciences, University of New South Wales, New South Wales, Sydney 2052, Australia

    • Ruby C. Y. Lin
  3. Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney 2010, Australia

    • D. Ross Laybutt
  4. Department of Anatomy, School of Medical Sciences, University of New South Wales, New South Wales, Sydney 2052, Australia

    • Romain Barres
  5. School of Paediatrics and Reproductive Health, University of Adelaide, South Australia 5005, Australia

    • Julie A. Owens

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Contributions

S.F.N. and M.J.M. designed the study. S.F.N. performed animal work, histology, islet harvest and RNA extraction, data analysis and wrote the manuscript. M.J.M. supervised the project and wrote the manuscript. R.C.Y.L. conducted microarray data analysis. D.R.L. assisted with islet harvest. R.B. conducted bisulphite sequencing and DNA methylation analysis. J.A.O. conducted ingenuity analysis and wrote the manuscript. All authors contributed to data interpretation, reviewed the manuscript and approved the final version.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Margaret J. Morris.

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    Supplementary Information

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DOI

https://doi.org/10.1038/nature09491

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