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

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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Figure 1: HFD leads to adiposity, glucose intolerance and insulin resistance in fathers.
Figure 2: Female offspring demonstrate impaired glucose tolerance and insulin secretion to a glucose challenge.

Accession codes

Primary accessions

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.

References

  1. Wang, Y. & Lobstein, T. Worldwide trends in childhood overweight and obesity. Int. J. Pediatr. Obes. 1, 11–25 (2006)

    Article  Google Scholar 

  2. Pinhas-Hamiel, O. & Zeitler, P. The global spread of type 2 diabetes mellitus in children and adolescents. J. Pediatr. 146, 693–700 (2005)

    Article  Google Scholar 

  3. Whitaker, R. C., Wright, J. A., Pepe, M. S., Seidel, K. D. & Dietz, W. H. Predicting obesity in young adulthood from childhood and parental obesity. N. Engl. J. Med. 337, 869–873 (1997)

    Article  CAS  Google Scholar 

  4. Morris, M. Early life influences on obesity risk: maternal overnutrition and programming of obesity. Expert Rev. Endocrinol. Metab. 4, 625–637 (2009)

    Article  Google Scholar 

  5. Tarquini, B., Tarquini, R., Perfetto, F., Cornelissen, G. & Halberg, F. Genetic and environmental influences on human cord blood leptin concentration. Pediatrics 103, 998–1006 (1999)

    Article  CAS  Google Scholar 

  6. Power, C., Li, L., Manor, O. & Davey Smith, G. Combination of low birth weight and high adult body mass index: at what age is it established and what are its determinants? J. Epidemiol. Community Health 57, 969–973 (2003)

    Article  CAS  Google Scholar 

  7. Bouchard, C. Childhood obesity: are genetic differences involved? Am. J. Clin. Nutr. 89, 1494S–1501S (2009)

    Article  CAS  Google Scholar 

  8. Guo, Y. F. et al. Assessment of genetic linkage and parent-of-origin effects on obesity. J. Clin. Endocrinol. Metab. 91, 4001–4005 (2006)

    Article  CAS  Google Scholar 

  9. Le Stunff, C., Fallin, D. & Bougneres, P. Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity. Nature Genet. 29, 96–99 (2001)

    Article  CAS  Google Scholar 

  10. Gluckman, P. D. et al. Towards a new developmental synthesis: adaptive developmental plasticity and human disease. Lancet 373, 1654–1657 (2009)

    Article  Google Scholar 

  11. Li, L., Law, C., Lo Conte, R. & Power, C. Intergenerational influences on childhood body mass index: the effect of parental body mass index trajectories. Am. J. Clin. Nutr. 89, 551–557 (2009)

    Article  CAS  Google Scholar 

  12. Dunn, G. A. & Bale, T. L. Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice. Endocrinology 150, 4999–5009 (2009)

    Article  CAS  Google Scholar 

  13. Ghanayem, B. I., Bai, R., Kissling, G. E., Travlos, G. & Hoffler, U. Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity. Biol. Reprod. 82, 96–104 (2009)

    Article  Google Scholar 

  14. Kasturi, S. S., Tannir, J. & Brannigan, R. E. The metabolic syndrome and male infertility. J. Androl. 29, 251–259 (2008)

    Article  CAS  Google Scholar 

  15. Figueroa-Colon, R., Arani, R. B., Goran, M. I. & Weinsier, R. L. Paternal body fat is a longitudinal predictor of changes in body fat in premenarcheal girls. Am. J. Clin. Nutr. 71, 829–834 (2000)

    Article  CAS  Google Scholar 

  16. Leibel, N. I., Baumann, E. E., Kocherginsky, M. & Rosenfield, R. L. Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. J. Clin. Endocrinol. Metab. 91, 1275–1283 (2006)

    Article  CAS  Google Scholar 

  17. Jimenez-Chillaron, J. C. et al. Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58, 460–468 (2009)

    Article  CAS  Google Scholar 

  18. Sone, H. & Kagawa, Y. Pancreatic β cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48, 58–67 (2005)

    Article  CAS  Google Scholar 

  19. Henquin, J. C., Nenquin, M., Ravier, M. A. & Szollosi, A. Shortcomings of current models of glucose-induced insulin secretion. Diabetes Obes. Metab. 11 (suppl. 4). 168–179 (2009)

    Article  CAS  Google Scholar 

  20. Wang, Z. & Thurmond, D. C. Mechanisms of biphasic insulin-granule exocytosis—roles of the cytoskeleton, small GTPases and SNARE proteins. J. Cell Sci. 122, 893–903 (2009)

    Article  CAS  Google Scholar 

  21. Fujisawa, T., Joshi, B., Nakajima, A. & Puri, R. K. A novel role of interleukin-13 receptor α2 in pancreatic cancer invasion and metastasis. Cancer Res. 69, 8678–8685 (2009)

    Article  CAS  Google Scholar 

  22. David, M., Bertoglio, J. & Pierre, J. TNF-α potentiates IL-4/IL-13-induced IL-13Rα2 expression. Ann. NY Acad. Sci. 973, 207–209 (2002)

    Article  ADS  CAS  Google Scholar 

  23. Zhang, X. Y. et al. The major histocompatibility complex class II promoter-binding protein RFX (NF-X) is a methylated DNA-binding protein. Mol. Cell. Biol. 13, 6810–6818 (1993)

    Article  CAS  Google Scholar 

  24. Lindsay, R. S. et al. Type 2 diabetes and low birth weight: the role of paternal inheritance in the association of low birth weight and diabetes. Diabetes 49, 445–449 (2000)

    Article  CAS  Google Scholar 

  25. Hypponen, E., Smith, G. D. & Power, C. Parental diabetes and birth weight of offspring: intergenerational cohort study. Br. Med. J. 326, 19–20 (2003)

    Article  Google Scholar 

  26. Hattersley, A. T. & Tooke, J. E. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 353, 1789–1792 (1999)

    Article  CAS  Google Scholar 

  27. Sharpe, R. M. Environmental/lifestyle effects on spermatogenesis. Phil. Trans. R. Soc. Lond. B 365, 1697–1712 (2010)

    Article  CAS  Google Scholar 

  28. Robertson, S. A. Seminal plasma and male factor signalling in the female reproductive tract. Cell Tissue Res. 322, 43–52 (2005)

    Article  Google Scholar 

  29. Aitken, R. J., Koopman, P. & Lewis, S. E. Seeds of concern. Nature 432, 48–52 (2004)

    Article  ADS  CAS  Google Scholar 

  30. Du Plessis, S. S., Cabler, S., McAlister, D. A., Sabanegh, E. & Agarwal, A. The effect of obesity on sperm disorders and male infertility. Nature Rev. Urol. 7, 153–161 (2010)

    Article  Google Scholar 

  31. Prior, L. J., Velkoska, E., Watts, R., Cameron-Smith, D. & Morris, M. J. Undernutrition during suckling in rats elevates plasma adiponectin and its receptor in skeletal muscle regardless of diet composition: a protective effect? Int. J. Obes. (Lond) 32, 1585–1594 (2008)

    Article  CAS  Google Scholar 

  32. Chamson-Reig, A., Thyssen, S. M., Arany, E. & Hill, D. J. Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific. J. Endocrinol. 191, 83–92 (2006)

    Article  CAS  Google Scholar 

  33. Lacy, P. E. & Kostianovsky, M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 16, 35–39 (1967)

    Article  CAS  Google Scholar 

  34. Laybutt, D. R. et al. Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to β-cell survival during chronic hyperglycemia. Diabetes 51, 413–423 (2002)

    Article  CAS  Google Scholar 

  35. Laybutt, D. R. et al. Critical reduction in β-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes. J. Biol. Chem. 278, 2997–3005 (2003)

    Article  CAS  Google Scholar 

  36. Irizarry, R. A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003)

    Article  Google Scholar 

  37. Huang, da W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57 (2009)

    Article  CAS  Google Scholar 

  38. Dennis, G., Jr et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol. 4, P3 (2003)

    Article  Google Scholar 

  39. Saeed, A. I. et al. TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34, 374–378 (2003)

    Article  CAS  Google Scholar 

  40. Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000)

    Article  CAS  Google Scholar 

  41. Olek, A., Oswald, J. & Walter, J. A modified and improved method for bisulphite based cytosine methylation analysis. Nucleic Acids Res. 24, 5064–5066 (1996)

    Article  CAS  Google Scholar 

  42. Grunau, C., Schattevoy, R., Mache, N. & Rosenthal, A. MethTools—a toolbox to visualize and analyze DNA methylation data. Nucleic Acids Res. 28, 1053–1058 (2000)

    Article  CAS  Google Scholar 

Download references

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.

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Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Margaret J. Morris.

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The authors declare no competing financial interests.

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Ng, SF., Lin, R., Laybutt, D. et al. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467, 963–966 (2010). https://doi.org/10.1038/nature09491

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