The scientific literature already contains robust evidence that obesity, whether maternal or paternal, can lead to metabolic changes in offspring that increase their risk of developing diseases. A new study published in the journal Nature Communications reveals the mechanism by which this "inheritance" is transmitted to the embryo by the father via the sperm.
In experiments with mice, the authors observed that the offspring of obese males were born at a normal weight. However, as the days passed, they exhibited glucose intolerance and insulin resistance, which can lead to type 2 diabetes. This condition is called "silent metabolic dysfunction."
The good news is that when the parents lost weight, the "marks" left by obesity in the semen disappeared – a finding that was later validated in human analyses.
Biochemist Jan-Wilhelm Kornfeld, a professor at the University of Southern Denmark (SDU), coordinated the study, which involved researchers from the State University of Campinas (UNICAMP) in Brazil led by Marcelo Mori . The Brazilian group is supported by FAPESP through three projects ( 21/08354-2 , 23/01703-7 , and 13/07607-8 ).
"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.
According to the researcher, male offspring were more affected than females, possibly because they are more susceptible to metabolic problems. "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."
Chemical messengers
During the tests, the researchers noted that the animals that became obese from a high-fat diet began overexpressing a type of microRNA known as let-7 in their adipose tissue (specifically the let-7d and let-7e variants). MicroRNAs are small RNA molecules that function as gene modulators, meaning they regulate the amount of proteins produced by cells.
Excess let-7 was also observed in the sperm of the obese males, and these molecules were transferred to the zygote during fertilization. In the embryo, the excess let-7 inhibited the production of DICER, an essential enzyme for the maturation of several other microRNAs and crucial for regulating many genes.
Without DICER, the embryo's cells develop with impaired functioning of the mitochondria, the organelles responsible for producing cellular energy. This mitochondrial dysfunction permanently alters how the offspring's adipose tissue handles energy, resulting in the glucose intolerance observed in adulthood.
"Something we still need to discover is how these microRNAs [let-7] also increase in sperm and where they come from. It's possible that they're transferred from adipose tissue to the reproductive cell, as suggestive evidence indicates, but that remains an open question," says Mori.
At UNICAMP, Mori's group is investigating how a decline in DICER enzyme expression in adipose tissue – which may result from aging or obesity – accelerates degenerative processes that lead to chronic diseases, such as diabetes.
"We believe that the loss of this enzyme may trigger metabolic dysfunction. On the other hand, we observed in previous studies that interventions that promote health and longevity, such as physical activity, induce an increase in DICER expression," says Mori (read more at agencia.fapesp.br/34783 ).
Complementary experiments
To prove that an increase in let-7 expression in fathers is sufficient to cause metabolic changes in offspring, the researchers injected the molecule into zygotes from healthy, lean animals. The results confirmed that the injection of this microRNA alone triggered in the offspring all the metabolic dysfunctions previously observed in the experiment with obese animals.
To determine if this was reversible, obese male mice were placed on a standard diet. After about nine weeks, the time needed for their weight to normalize, the excess let-7 microRNA disappeared from both adipose tissue and sperm. When these slimmed-down males were bred, the researchers observed that their offspring were born just as healthy as those in the control group that had never been overweight.
To validate these findings in humans, the researchers evaluated 15 men with severe obesity (average BMI close to 40) who were preparing for fertility treatments. Initial analyses showed excess let-7 in both adipose tissue and semen. After undergoing a six-month lifestyle intervention and dietary reeducation, the microRNA levels decreased significantly.
"The results show that the more weight the individual lost, the lower their let-7 levels in semen," says Mori.
According to Kornfeld, there is ample evidence – and this study is yet another example – that sperm reflects male health in some way. "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."
About São Paulo Research Foundation (FAPESP)
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