Epigenetics of obesity

Hereditary obesity does not always depend on genes

Kirill Stasevich, "Science and Life"

It is known that metabolic disorders that can lead to obesity and diabetes often develop due to genetic mutations: a corrupted gene ceases to properly monitor metabolism, and because of this, problems begin with glucose uptake, with insulin, with adipose tissue, etc. (One of the most well-known and most studied here is the FTO (fat mass and obesity-associated protein) gene – some variants of FTO add an average of three extra kilograms to its carriers).

Such a gene, once it has arisen, can pass from generation to generation for quite a long time, so that all members of the genus along some line, maternal or male, will have to closely monitor the waist and blood sugar levels.

However, genes never work on the principle of "on/off", they always have some range of activity. In other words, a gene can work weakly, not very weakly, moderately strongly, etc. The way a gene is configured to work depends on mutations, but also on external and internal factors – that is, roughly speaking, on our lifestyle with ecology and on the activity of other genes. So, if we go back to obesity, it is not always associated with a genetic "curse" – improper nutrition may well change the metabolism for the worse without any mutations.

Living organisms have a lot of molecular ways to adjust the activity of genes, and many of these mechanisms do not function for long – after working for some time in some force majeure circumstances, the gene returns to its normal state. However, it also happens that changes in genetic activity persist for life, and even, moreover, are transmitted to the next generation. At the same time, we emphasize that the gene itself does not change, its DNA does not change, no mutations occur, just regulatory molecules do not let go of their grip.

Such cases are called epigenetic regulation, and, as studies by Johannes Beckers and his colleagues from the Munich Center show. According to Helmholtz's Environmental and Health Research, obesity can be transmitted from generation to generation precisely with the help of epigenetics (You Are What Your Parents Ate!). That is, the consequences of an unhealthy lifestyle of parents can pass on to their descendants, despite the fact that the actual genes of both will be quite ordinary, without mutant changes.

The researchers kept genetically identical male and female mice on three different diets for six weeks: fatty, normal and low-fat. As expected, the animals that were fed fat got obese and the first signs of type 2 diabetes. Then, germ cells were taken from all mice for in vitro fertilization. The procedure itself was carried out in all possible combinations: a sperm from a "fat" male was reduced to an egg from a female on a regular diet, then a sperm from the same male was reduced to an egg from a female on a low-fat diet, etc. The embryos were implanted into healthy females, and then, when the mice were born, they were nine weeks old they were fed regular food, without fat distortions, and then they were still transferred to fatty foods.

Fatty foods added weight to everyone, but, as stated in an article in Nature Genetics (Huypens et al., Epigenetic germline inheritance of diet-induced obesity and insulin resistance), the amount of excess weight clearly depended on what the parents ate. For example, females born from "fat" males and females were 20% thicker than the offspring of normal mice (that is, those who were fed regular food). In general, according to the authors of the work, dependence on the parental diet was most pronounced in daughters.

Another interesting point concerns glucose metabolism: it is known that one of the harbingers of type II diabetes is the loss of insulin sensitivity by tissues and organs and, as a result, the inability to cope with elevated blood glucose levels. In the experiment, problems with sugar passed from one generation to another mainly through the maternal line: if at least only the mother suffered from overweight, then her descendants, both "boys" and "girls", had a higher probability of sugar-insulin troubles than in all other cases (that is, if overweight he was only with his father, and his mother was on a normal or low-fat diet, etc.). Just in case, we recall once again that genetically all the parent mice were the same and without "obese" mutations, and the predisposition to overweight in young mice was the result of gene tuning formed in the previous generation.

This is far from the first work that talks about the epigenetic inheritance of obesity and related metabolic problems, there are both statistical and experimental data on this. However, until now, in experimental studies, mice were simply crossed and their offspring were observed, and in this case it remains likely that obesity in the next generation arose not because of epigenetic factors, not because the parents ate fatty foods, but because of the peculiarities of embryonic development. One can, for example, imagine that in females, obesity affects the physiology of the uterus, which, in turn, affects the embryo. In the case of in vitro fertilization and when using a normal, healthy female as a surrogate mother – as in the work described above – such ambiguities can be avoided.

Now it would be interesting to find out in the same way whether such obesity can be transmitted to the second and third generations, and how long parents should live on the wrong diet in order for epigenetic mechanisms to consolidate a new unhealthy "metabolic reality". And, of course, the question remains, what specific molecules are involved here. Now there are several molecular devices that can change the activity of genes for a very long time: these are enzymes responsible for DNA methylation and demethylation; enzymes that modify histones – chromosomal proteins that control the archiving and unarchiving of DNA; and a complex of regulatory RNAs. We will not go into the details of each mechanism, we will only say that for a long time it was unclear whether such mechanisms work in the precursors of germ cells in mammals. However, there are already known examples that they really work there – that is, epigenetic changes may well cross the intergenerational boundary.

Finally, the most pressing question is: to what extent can the data obtained be applied to people? Molecular processes at this level are usually quite universal, and if an example of inherited epigenetic regulation could be found in mice, there is a high probability that the same can be found in most animals, including humans.

The only question is how to find this "same thing": we mentioned the problems associated with transferring laboratory results to people when we wrote about the work on the effect of stress on epigenetics. There is no need to count on experiments here, it remains to rely only on medical statistics and mass genetic analysis.

Portal "Eternal youth" http://vechnayamolodost.ru  17.03.2016