Health before pregnancy is often discussed as a maternal issue, but a growing body of research suggests fathers’ health may matter before conception, too.
A new study in Nature Communications adds to that conversation by identifying a possible biological pathway linking paternal obesity with metabolic changes in offspring. In experiments with mice, researchers found that obesity in male animals altered small molecules in sperm, which were then linked to prediabetes-like changes in their offspring. The study also found that those sperm changes appeared to reverse after male mice lost weight.
The findings are not proof that the same process causes metabolic problems in human children. Most of the study was conducted in mice, while the human portion looked only at molecular changes in semen from a small group of men with severe obesity. Still, the research offers a closer look at how a father’s metabolic health before conception may influence early development.
The study was coordinated by Jan-Wilhelm Kornfeld, a professor at the University of Southern Denmark, with researchers from the State University of Campinas in Brazil and other collaborators. The team focused on microRNAs, small molecules that help regulate how genes are expressed.
“We monitored the development of the offspring [of obese males] for six months and noticed that, although the animals showed no changes in weight, their metabolism was compromised as if they were obese,” Kornfeld told Agência FAPESP.
In the mouse experiments, male animals with obesity had higher levels of a type of microRNA called let-7 in their adipose tissue, or body fat, and in their sperm. When these males reproduced, their offspring were born at a normal weight. Over time, however, the offspring developed signs of impaired metabolism, including glucose intolerance and insulin resistance, which are warning signs linked to type 2 diabetes risk.
Male offspring were more strongly affected than female offspring. Kornfeld said female animals also showed a tendency toward metabolic dysfunction, but it was less pronounced.
“In the case of females, we also noticed a tendency [toward metabolic dysfunction], but it wasn’t as pronounced as in males. It’s like in humans: women are metabolically more resilient.”
The researchers traced the effect to a pathway involving let-7 and an enzyme called DICER. In the study, excess let-7 appeared to interfere with DICER in the embryo. DICER is involved in the maturation of other microRNAs and helps regulate many genes. When this process was disrupted, the researchers found changes in mitochondrial function in the offspring’s adipose tissue. Mitochondria are the energy-producing structures inside cells, and impaired mitochondrial function can affect how tissue handles energy.
To test whether let-7 itself could drive the changes, the researchers injected the molecule into embryos from lean, healthy mice. The offspring later developed metabolic problems similar to those seen in the offspring of obese males. That experiment strengthened the case that let-7 may play a causal role in the mouse model.
The study also looked at whether the effect could be reversed. Obese male mice were switched to a standard diet for about nine weeks, until their weight normalized. After weight loss, excess let-7 disappeared from their adipose tissue and sperm. When those males reproduced, their offspring appeared as healthy as offspring from the control group of males that had not had obesity.
For human context, the researchers studied 15 men with severe obesity who were preparing for fertility treatment. Before a six-month lifestyle intervention and dietary reeducation program, the men had excess let-7 in adipose tissue and semen. After the intervention, let-7 levels decreased significantly, and greater weight loss was linked with lower let-7 levels in semen.
“The results show that the more weight the individual lost, the lower their let-7 levels in semen,” said Marcelo Mori, a researcher at the State University of Campinas.
That human finding is important but limited. It suggests that semen may reflect changes in metabolic health, but it does not show whether those changes affected embryos, pregnancies or children’s health. The study also does not mean fathers with obesity will have children with metabolic disease, or that weight loss before conception guarantees healthier outcomes.
The more careful takeaway is that sperm may carry signals shaped by a father’s metabolic state, and some of those signals may be flexible. That could eventually broaden how researchers and clinicians think about preconception health.
Kornfeld said the study adds to evidence that sperm may reflect male health in ways that matter for reproduction.
“Everything indicates that it’s less advantageous to have children when stressed or infected, when too many or too few calories are being eaten, or when facing any other health issue. Children conceived under unbalanced conditions tend to be less healthy.”
This research was supported by several international research organizations and institutions, including the European Research Council, the University of Southern Denmark, the Danish Diabetes and Endocrine Academy, the Novo Nordisk Foundation, National Taiwan University, Taiwan’s National Science and Technology Council, the São Paulo Research Foundation, Brazil’s National Council for Scientific and Technological Development, Brazil’s federal agency for graduate education support and the Swedish Research Council. Some single-cell sequencing work was partly supported by CellX, the Danish Single-Cell Examination Platform, funded through Denmark’s national research infrastructure program.