There is already robust scientific 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 multinational team of researchers observed that the offspring of obese males were born at a normal weight.
However, as the days passed, the young mice 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 fathers lost weight, the “marks” left by obesity in the semen disappeared – a finding that was later validated in human analyses.
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According to study corresponding author and University of Southern Denmark biochemist Prof Dr Jan-Wilhelm Kornfeld, 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,” he said.
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.
MicroRNAs are small RNA (ribonucleic acid) 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 fertilisation.
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.
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 normalise – 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 study co-author and Brazil’s State University of Campinas (UNICAMP) molecular biologist Associate Prof Dr Marcelo Mori.
According to Prof 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.”– By Karina Toledo/Agência FAPESP
