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PHYSIOLOGY

Weight across generations

Among rats, effects of excessive or insufficient feeding can be transmitted to children and grandchildren

NegreirosExperiments on rats conducted by researchers from universities in São Paulo reinforce the idea that being overweight may be a phenomenon that transcends generations, and not just because children tend to inherit genes from their parents that favor the accumulation of calories and predispose them to obesity, or because they live in an environment in which there is an excessive amount of food available. Through mechanisms that are still poorly understood, alterations in the food supply for females shortly before or during pregnancy seem to increase the likelihood of having overweight children and even grandchildren.

In a series of experiments, biologist Maria Martha Bernardi and her team at Paulista University (UNIP) fed a high-calorie diet to some female rats at the start of their reproductive lives and to others that were already pregnant and waited to see what would happen to the first generation of pups and to the offspring of these pups. Both the rodents that were born from overfed mothers and those from the following generation showed a greater tendency to become overweight.

The tendency towards excessive weight gain even occurred when the children and grandchildren of these rats were only fed the standard laboratory diet. According to Bernardi, those results indicate that the period in which the fetus is developing in the uterus is crucial in defining the metabolic regulation of that animal as well as at the metabolic regulation of at least the following generation.

If those changes only appeared in the first generation, the most natural conclusion would be that hormonal alterations caused by the maternal diet had affected the pups. However, since this effect continues into the second generation, researchers suspect that the propensity to gain weight may be maintained by epigenetic mechanisms: alterations in the way genes are turned on and off, caused by environmental factors, such as diet, and transmitted to the following generations. Those changes to the profile of gene activation do not directly alter the sequence of “chemical letters” of DNA, even though they were inherited over generations. Although Bernardi’s group has not analyzed the gene activity pattern, data obtained by scientists all over the world indicate that changes to the gene activation profile, without alteration to the DNA sequence, may occur in both animals and human beings.

Fattening diet
Interestingly, it was not just maternal overfeeding during gestation that seems to have affected their gene activation profile and left children and grandchildren with a tendency to gain weight. In one of the experiments, conducted in partnership with researchers from the University of São Paulo (USP), the Federal University of the ABC (UFABC) and the University of Santo Amaro (UNISA), 12 female rats received 40% less food than what is considered normal for these pregnant rodents, while eight rats from the control group were fed with the normal laboratory diet.

The female rats that went hungry during pregnancy gained less than half the weight of the females that could eat whatever they wanted. The offspring of the mothers submitted to feeding restrictions were born smaller and continued to be thinner for some time, even though they received the same amount of food as the offspring of the rats that did not go hungry. The difference only disappeared when they entered adulthood, and the two groups of rodents attained similar weights, although the offspring of the hungry rats had a higher percentage of body fat, especially a type of fat that accumulated between organs (visceral fat), which is associated with a higher risk of cardiovascular problems.

NegreirosThe most important difference appeared in the second generation. The grandchildren of rats who ate little while they were pregnant were born smaller, but when they became adults, they were slightly heavier (from 10% to 15%) than the grandchildren of the rats that were fed normally. They had more visceral fat, as well as signs of inflammation in their brains. That extra weight gain occurred even though the females of the first generation, which were therefore the mothers of these animals, were fed normally. It is as if the deprivation of food suffered by the rats in the initial generation caused a lasting metabolic reprogramming in their descendants, say the researchers in an article published in May 2016 in the journal Reproduction, Fertility and Development.

With regard to this point, the work done by the São Paulo team confirms previous studies that had already found an association between episodes of hunger during pregnancy and the birth of children with a propensity for gaining excess weight and the health problems associated with it. Although they did not identify the specific mechanism behind this effect, Martha Bernardi and her team suspect that compounds produced by the bodies of the original generation mothers, deprived of food during pregnancy, activate genes that favor rapid weight gain in the pups. Thus, the chemical signals released by the maternal body act as a kind of warning that there is scarcity in the environment, and that the available food resources must be used as efficiently as possible. That signal, received by the pups’ organisms, could make all the difference, representing the chance to grow and survive in an environment with limited food. “But it can also lead to obesity, if the food supply returns to normal after they are born,” explains Bernardi.

Studies conducted in previous decades showed a situation that is very similar to the one described above among the descendants of women who became pregnant during the so-called Hongerwinter (winter of hunger, in Dutch), when the Nazi armies that were retreating from the advancing Allies cut off a large part of the food supplies to Holland between late 1944 and early 1945, at the end of World War II. Both the children and grandchildren of Hongerwinter survivors had obesity rates and metabolic problems that were higher than those expected for the general population.

Inflammation in the brain
In another study, Bernardi and her colleagues gave hypercaloric feed – a mixture of standard feed plus a liquid supplement rich in different types of fat to 10 female rats right after they were weaned, while another group of female rats received normal feed and served as the control group. As expected, the female rats fed the hypercaloric diet when they were babies were overweight, albeit not obese, when they reached puberty. Similar effects were observed in their daughters: they were rats that as adults were overweight and suffered from metabolic alterations, such as the accumulation of visceral fat, although they had only been fed a balanced diet throughout their entire lives. Also published in Reproduction, Fertility and Development, that study, and others by the group indicate that being overweight was what started the inflammatory processes that affected the brains of the mother and her offspring, in an apparently lasting manner.

If it seems strange to imagine that excess weight can lead to cerebral inflammation, it must be remembered that fat cells are more than just mere deposits of calories. Adipocytes, as they are called, produce a large variety of substances, including molecules that cause inflammation, which reach the bloodstream and from there the hypothalamus, the region of the brain associated with several functions, including controlling hunger.

Studies not yet published by the UNIP group also indicate that this inflammation can affect other areas of the rodents’ brains. The researchers hypothesize that the process of inflammation in the brain is related to the reprograming of the body transmitted from the mother to her pups, including alterations in appetite control, which may continue throughout adult life.

NegreirosFor Alicia Kowaltowski, a researcher at the USP Chemistry Institute, who studies the relation between diet and the mechanisms of energy production in cells, there is a fairly strong likelihood that the tendency to become overweight and obese is passed from one generation to another through means that do not involve inheriting genes that favor weight gain. “The question is to find out which mechanisms are behind these phenomena,” states the researcher.

Among these potential mechanisms, one that has attracted more interest are epigenetic transformations. The Greek prefix epi means superior, and the word epigenetics, coined in the 1940s by English embryologist Conrad Waddington, designates the branch of biology that studies the chemical changes caused by the environment that lead to activation or inactivation of genes and alter the functioning of body. One of the more common chemical modifications that genes undergo is called methylation. In it, a methyl group, formed by one carbon atom and three hydrogen atoms (CH3), attaches itself to a section of DNA, preventing it from being read by the cell machinery. The result is the silencing of that region. Studies with dozens of species of animals, plants and fungi have already shown that the methylation profile can be transmitted from one generation to another, and can affect the characteristics of the offspring.

Paternal influence
The role mothers play in overweight offspring seems to be ever clearer. But what about the role of the fathers? “There is some evidence that there may also be a paternal influence, but this evidence is not as clear,” says Martha Bernardi. On the one hand, it would make sense for epigenetic influences to be able to be transmitted paternally–as with other cells in the body, sperm can be affected by alterations in the gene activation pattern produced by environmental influence. If these changes are not totally eliminated after the male cells and the ova come together, the new individual created by this fertilization could carry part of its father’s epigenetic memory.

A 2015 study conducted by a team from the University of Copenhagen, Denmark, led by Romain Barrès, showed that this scenario is plausible by studying the sperm of 16 obese men and the sperm of 10 normal weight men. In the case of the obese volunteers, the epigenetic patterns, like the methylation patterns, were concentrated in genes related to nervous system development, especially those that are important for controlling appetite (and therefore, weight), which did not occur with the thin men.

Barrès and his colleagues suggested another comparison between the epigenetic markings of the sperm of obese men before they underwent bariatric surgery and the markings of these same participants after the operation. The result: after the surgery, the epigenetic pattern of the cells was similar to that of normal weight men.

“The most important aspect of these discoveries is that they suggest that these modifications can occur in germinal cells; that is, ova and sperm, and that they can be transmitted to future generations,” says physician Licio Augusto Velloso, a professor at the School of Medical Sciences of the University of Campinas (FCM-Unicamp), who studies the cellular and molecular mechanisms related to the origin of obesity and diabetes. “Epigenetic studies have advanced a great deal in the last decade, and it is hoped that in a not-too-distant future, the mapping of environmental factors and their impact on different aspects of epigenetics will help us to prevent important diseases,” affirms Velloso.

Seeing excess weight from the prism of epigenetics can bring another relevant piece to the jigsaw puzzle of the global epidemic of obesity and of related metabolic diseases. Historically associated with health and plenty, excess weight has become a problem of major proportions, first in rich countries, but today, it is becoming ever more common in poorer countries–beginning with Brazil, where almost 60% of the adult population is above the weight considered healthy, according to data from of the Brazilian Institute of Geography and Statistics (IBGE). Many developing countries quickly transitioned from a context in which malnutrition was a serious problem into another, in which obesity is a much greater concern.

Scientific articles
JOAQUIM, A. O. et al. Maternal food restriction in rats of the F0 generation increases retroperitoneal fat, the number and size of adipocytes and induces periventricular astrogliosis in female F1 and male F2 generations. Reproduction, Fertility and Development. 31 May 2016.
JOAQUIM, A. O. et al. Transgenerational effects of a hypercaloric diet. Reproduction, Fertility and Development. 25 Aug. 2015.

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