How dad’s diet could affect his child’s lifelong metabolism

There is heaps of guidance on what would-be mothers should eat both before and after conception to ensure a healthy future for their baby. But research in animal models suggest that the father’s diet deserves attention as well, since a father’s diet before conception seems to have effects that can reverberate through generations.

Previous studies have found that the father’s diet affects children’s metabolism, risk of cancer and all-cause mortality but have not clearly determined which aspects of the diet trigger these changes. Is it the fat in a high-fat diet or a deficiency of other macronutrients such as protein or carbohydrate?

Research published in Nature Communications used a special analytical technique to triangulate the macronutrients that cause a mouse father’s diet to affect his offspring’s metabolism – and found that daughters are affected but sons are spared from metabolic effects.

Although we are still “quite far away” from understanding how this could translate to humans, the findings have important implications for how the genome can “adapt to new environmental conditions,” says co-author Romain Barrès, a molecular biologist and physiologist at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark.

Dad, the epigenome and you

Since scientists cannot intervene in multiple generations of a human family’s diet the way they can with mice, researchers search for accidental experiments in the historical record for insight into how human parents’ diet affects their descendants.

Perhaps the most famous example is the village of Överkalix, located on the Arctic Circle in Sweden. In the 1900s, “it was so remote that having access to the crop registry and shipping records could inform you whether this population had good access to food in some years and poor access to food in others,” Barrès explains. In 2001, researchers analysed food availability in the 1900s, and by tracking down the fates of the descendants, “they could make a connection between the access to food in one generation and the risk of developing cardiovascular and metabolic diseases in the next generation,” Barrès says.

The mechanism for passing these changes down is called epigenetics – a system of chemical tags attached to DNA. The relationship between genetics and epigenetics is similar to a “cookbook”, Barrès says. “Our DNA is identical in all cells in our body, but what makes a cell different is the specific genes or recipes this cell is using.”

“This is like sticky notes you put on a recipe book that signal where to look and what recipe to use.”

And just like sticky notes in a cookbook, these epigenetic tags on DNA can be added, removed or altered over time according to need. “Our research examines how diet and physical exercise affect how we change the epigenetic make-up of various cells and what is transmitted from one generation to the next,” Barrès says.

The diet of both parents affects their children’s metabolism, but dad’s diet is easier to disentangle from what happens during gestation, Barrès says. A father’s contribution is a snapshot in time of the father’s epigenetic state from just before conception.

Nutritional triangulation

Previous studies have manipulated the diet of male mice to see how it affected their offspring’s metabolism. “Many use a diet paradigm in which they change one parameter at a time” – for instance, reducing carbohydrate, Barrès says. But the problem is “when you change only one parameter at a time, you do not really change just one parameter at a time for the exact same number of calories.”

“If I give you a high-fat diet, it has to be lower in something – potentially protein and carbohydrate – because it cannot be high in everything,” he says.

To overcome this issue, Barrès’ co-author Stephen Simpson from the University of Sydney in Australia has developed a workaround he calls the Nutritional Geometry Framework that uses a wider variety of diets with incremental differences to pin down which macronutrients might cause a given effect.

“If you have enough different diets in one experiment, you can keep one macronutrient the same – say, protein – and have several diets that vary in carbohydrate,” Barrès says. “If the response to these diets is the same, you can conclude that protein is an important factor.”

To investigate which macronutrients might cause generational metabolic changes, Barrès and his team fed male mice 10 diets varying in protein, carbohydrate and fat composition. “We gave those to male mice for a few weeks before conception, mated them with female mice fed a standard diet and then studied the offspring,” he says.

“We found sex-specific transmission,” Barrès says.

The researchers observed that the fat composition of a mouse father’s diet affected the metabolism of his daughters but not his sons. Female mice whose fathers had eaten a high-fat diet before conception had higher body fat and more difficulty regulating their blood glucose.

Why the sexes differ so dramatically is a “million-dollar question for this field,” Barrès says. “But this is very consistent across many, many studies from many groups.” Some researchers have theorised that the difference could involve interactions with hormones or a difference in the levels of expression of key genes.

How this could translate to humans

These findings should not be taken as a mandate for would-be human dads to radically change their lifestyles before they start trying to conceive, Barrès says. Although the primary result of this study – that a mouse dad’s poor diet negatively affects his daughter’s health – is fairly intuitive, this is not always the case in epigenetics.

Other experiments with mice have shown how having a dad in peak physical condition before conception may not be the boon we imagine.

In one study, researchers let mice run up in wheel cages. They ran more than 10 km per day – “for us, this would translate into an ultramarathon per day,” he says. “Their offspring had more capacity to get obese, develop metabolic dysfunction and other problematic conditions.”

At first blush, that could be surprising, Barrès says. “You think exercise is good, so if the father’s had a good lifestyle, the offspring should be healthy.” But it makes sense when you consider the evolutionary utility of epigenetic inheritance.

In the experiment with the distance-running mice, “you have dads who needed an important quantity of calories to run their ultramarathons,” he says. The metabolic shift that made the offspring more likely to build fat reflects an “increased capacity to store fuel – which is adaptive when an animal has to run a lot.”

In ideal situations, epigenetics functions to give offspring the best possible start in life by calibrating their genome to suit the environment their parents experienced. But that falls apart “if the environment has changed,” Barrès says – then those sticky notes in the epigenetic cookbook can hinder more than they can help.