A father’s weight is written into sperm – and can shape the child’s metabolism

Emil is nine years old and has struggled with his weight and blood glucose since he was young. The family eats healthily, keeps a close eye on meals and counts the calories in everything he eats. His parents cannot understand why his body so easily falls out of balance – even though they are doing everything right. The explanation may begin before he was even conceived.

Doctors and biologists have long been able to explain why a mother’s excess weight can affect her child’s health, because her metabolism helps to shape the environment in which the fetus develops during pregnancy. For fathers, the explanation has been far less clear.

Now, researchers at the University of Southern Denmark in Odense show that a father’s excess weight can also leave biological traces that follow the child from the very start of development. The findings have recently been published in Nature Communications.

The study was led by Jan-Wilhelm Kornfeld, Professor at the Department of Biochemistry and Molecular Biology and a researcher at the Center for Adipocyte Signalling of the University of Southern Denmark. He conducted the study together with colleagues from Denmark, Sweden, Germany, Poland, France, Taiwan, Brazil and the United States.

He describes the findings as important, although their significance currently lies in research rather than clinical practice.

“The field has long recognised the link, including for the father. What we lack is a biological explanation. With these new findings, we obtain a much clearer picture of how the father’s metabolism leaves its mark on the sperm cell – and thus on the child’s development,” says Jan-Wilhelm Kornfeld, continuing:

“The results point us in a new direction, because we can now track how obesity alters small molecules – microRNAs – in sperm cells, molecules that fine-tune which genes are switched on and off early in development.”

Designing an experiment that isolates the father’s effect

The biological explanation did not emerge on its own. Before the researchers could look for it, they had to design the experiment so that the father’s influence stood out as clearly as possible. The team therefore set up a mouse experiment in which everything related to the female mice and the upbringing of the offspring was kept constant while one factor was varied: the fathers’ diet and, consequently, their weight development.

This made the father’s excess weight the only systematic difference – and enabled changes in the offspring to be linked directly to the sperm.

The researchers divided the male mice into three groups. The first group was fed a low-fat diet throughout the experiment. The second group was fed a high-fat diet for 18 weeks and became overweight. The third group was first fed a high-fat diet and then switched to a low-fat diet, enabling the researchers to examine what weight loss meant for the biological traces.

The male mice were then mated with lean female mice living under identical conditions. The females were fed the same healthy diet, and all offspring were raised under the same conditions.

“We needed an experimental model in which we could track the biological changes in the father’s sperm step by step,” says Jan-Wilhelm Kornfeld.

From sperm signals to metabolic change

With the experimental model in place, the researchers could begin to measure how changes in sperm cells carried through to the next generation. They examined blood glucose, insulin sensitivity and weight in both the male mice and their offspring and then followed the signals into the tissues to see where the differences accumulated. Adipose tissue stood out most clearly and became the focus of the next analysis.

The mouse experiments revealed a consistent pattern. Overweight male mice produced offspring with poorer blood glucose regulation, lower energy expenditure in adipose tissue and changes in small RNA molecules in sperm, which help to regulate early development after fertilisation. The researchers point in particular to two microRNAs, let-7d and let-7e.

These appear to suppress DICER1, a key enzyme that regulates how microRNAs are formed – and thus, indirectly, which genes become active in the earliest stages of development.

The next step was to examine how these altered RNA molecules in sperm affect the embryo. The researchers therefore analysed embryos shortly after fertilisation to determine how early in development the changes could be detected.

The signal is present from the very start

In addition, the researchers tested directly whether the small RNA molecules in sperm were in themselves sufficient to alter development – without any other influence from the father. In this way, they were able to trace the link back to the very earliest stages of development in mice.

Finally, the researchers turned to humans. They analysed samples from 15 overweight men before and after weight loss to determine whether the same pattern could also be found in their sperm. Here, the same changes appeared in the small RNA molecules that had first been observed in mice, and the changes became less pronounced as the men lost weight.

This suggests that the same biological mechanism may also be present for humans – but for now only as a strong indication and not definitive proof.

“The dataset is still too limited for a definitive conclusion, but the results give us a clear direction for further work,” says Jan-Wilhelm Kornfeld.

Sons are most affected

The most striking finding is that fathers’ excess weight appears to affect sons most strongly in the first generation of offspring. The study cannot explain why the effect is more pronounced among sons than daughters – but it suggests that sex influences how these early signals are processed in the body.

The sex difference is therefore one question he and his colleagues will continue to investigate.

“This is a striking finding because it points to sons being particularly vulnerable. We can see the imprint from father to son, but we still need to understand why the sexes respond differently,” says Jan-Wilhelm Kornfeld.

For him, the significance of the study lies in the fact that researchers can now connect several stages of the same story. The father’s metabolism leaves an imprint on the sperm cell, which can be traced from the earliest stages of development through to the son’s ability to regulate blood glucose and burn energy – a chain stretching from molecule to metabolism.

This provides researchers with a biological pathway that can be examined step by step.

Tracing the biological path from father to child

Further, the results point to a more specific location in the body. The clearest changes accumulate in adipose tissue, which thus becomes more than simply the site where excess weight is stored. According to Kornfeld, this gives researchers a new place to look for an explanation of how the father’s metabolism ends up in the sperm cell and is passed on at fertilisation.

“It makes a difference that we now have a tissue and a biological process to work with. These are the kinds of results that can move a field forward,” he says.

For Kornfeld, the study also points to the reality beyond the laboratory. In mice, weight loss attenuated several of the biological markers, and in the small group of men, the same changes in semen followed a similar pattern. This suggests that prevention may begin before conception – because biological signals from the father are already present in the sperm at fertilisation.

“The results give us a reason to look at the period before conception in a new way. Here lies a line of research that could change our view of where prevention begins,” says Jan-Wilhelm Kornfeld.

This also shifts the nature of the final question. The study demonstrates fathers affecting children in the first generation. The next step is to clarify how strong this effect is for humans – and whether sons can pass it on to the next generation. The effect may therefore extend beyond a single generation.