Female offspring of male rats on bad diets are more likely to develop diabetes-like disease.
Fathers eating a fatty diet can pass on health problems to their female offspring, according to a study in rats published in Nature1.
The father's condition seems to be inherited without changes to the DNA code itself. Instead, there are 'epigenetic' chemical tweaks to the genes, altering how they are expressed in the offspring.
"We think this is one of the first findings in mammals where a nutritional effect in a father has been passed on to his offspring," says lead author Margaret Morris, a researcher in obesity and diabetes at the University of New South Wales in Sydney, Australia.
Globally, the prevalence of obesity in most age groups is increasing, and this is linked with an increase and early emergence in type 2 diabetes — a form of the disease that usually emerges in later life2.
Ample research has been done showing that if a mother's diet is poor and she is obese, this can damage her offspring's metabolism and increase their risk of obesity3. "But there's very little on the paternal influence. That's why this research is so important," says Neil Stickland, head of basic sciences at the Royal Veterinary College in London, who was not involved with the new study.
Morris and her team put one group of rats on a high-fat diet. A control group was fed a normal diet. Unsurprisingly, those on the high-fat diet became overweight and showed two hallmarks of type 2 diabetes. They had problems with glucose metabolism and were insulin resistant — effectively meaning that the hormone becomes less efficient at lowering blood sugar levels.
The real surprise came when Morris's team went on to examine the obese rats' female offspring. These too had problems regulating insulin and glucose levels. The healthy fathers, however, had correspondingly healthy daughters. Whether similar defects emerge in sons remains to be seen.
We think this is one of the first findings in mammals where a nutritional effect in a father has been passed on to his offspring. ,
Glucose levels in the body are controlled by insulin, produced by groups of β-cells in the pancreas. These cells group to form 'islets'. The team noticed that in the daughters of fat fathers, these islets had shrunk, compared with those of the control daughters.
The next step was to investigate what was causing these changes. The daughters of the obese male rats showed an altered expression of more than 600 pancreatic islet genes. But because the DNA code itself remained unchanged, Morris's team suggest that the changes in gene expression are epigenetic.
The researchers found the greatest difference in expression in a gene called Il13ra2. A gene's expression can be altered by methylation, in which methyl groups are added to the DNA, effectively 'silencing' the gene. But in the daughters of obese fathers, the level of methylation of this gene was around 25% of the level seen in the control daughters.
But not everyone is convinced. Stephen O'Rahilly, a clinical biochemist at the University of Cambridge, UK, notes that "the difference in glucose tolerance between these animals is pretty slim, and the number of animals in the study was too few to give a robust signal".
What's more, it's still not clear whether these changes are caused by a lifelong fatty diet, or whether there are crucial periods in a father's development when his sperm are affected by such a diet.
"What this study doesn't discern between is pubertal exposure and adult exposure in the father rats, because Morris's team covered the whole window," says Tracy Bale, a researcher in neuroscience at the University of Pennsylvania in Philadelphia whose work includes the epigenetics of disease. "So in humans, it does not mean that if a man eats a cheeseburger one night, and mates with his spouse the next day, that they will have a child with β-cell dysfunction. That would be remarkable."
Whether this study translates directly to humans remains to be seen. But many mothers are entering pregnancy either overweight or obese, and it is probably the case that many fathers are also having children while obese, says Morris. "Maybe that is affecting gametes in ways that are going to have consequences for the next generation," she says.
O'Rahilly warns that it would be "utterly premature" and "dangerous" to translate these findings to humans. "This is an interesting and provocative paper, but science eventually comes out in the wash." The result should be reasonably easy to reproduce across different labs, he adds. "If it is real, other people will find it."
Ng, S-F . et al. Nature 467, 963-966 (2010).
Wang, Y. & Lobstein, T. Int. J. Pediatr. Obes. 1, 11-25 (2006).
Morris, M. J. Expert Rev. Endocrinol. Metab. 4, 625-637 (2009).
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Marsh, G. Fat fathers affect daughters' health. Nature (2010). https://doi.org/10.1038/news.2010.553