THERE ARE genes strongly associated with BMI, and this is nothing new. Now, however, new rare mutations have been identified that seem to “protect” against obesity: in particular those that “inactivate” the GPR75 gene. The discovery is described on Science and it is actually double news. The interesting aspect of the study, in fact, is how these variants were identified: through a sequencing of the part of the DNA that carries the instructions for “building” proteins, called exome, carried out in over 640,000 people. An impressive analysis, decidedly on a large scale, which has two advantages: it allows to establish a very strong association and to quickly verify its impact. Thus accelerating the search for possible pharmacological solutions.
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The study was conducted by the US biotech company Regeneron in collaboration with several universities and research centers in the US, Mexico, the UK and Sweden, and adds an important new piece to understanding the genetics of obesity. “Obesity is often attributed to low willpower, laziness and gluttony, but science has shown that, beyond the importance of the environment we live in, lifestyle, healthy diet and physical exercise, genetic and biological factors play a very important role in the risk of becoming obese or, on the contrary, in the predisposition to remain thin “, he says to Salute Luca Lotta, Regeneron’s geneticist epidemiologist who led the study.
The mutations of obesity
To date, two types of studies on the genetics of obesity have been conducted, explains Lotta: the first have focused on families in which there were cases of early obesity and have made it possible to discover mutations (over twenty, ed.) Associated with an increased risk of becoming obese: “These mutations often occur in genes expressed in the brain, such as MC4R, which codes for a receptor that controls satiety. People with mutations that make a copy of MC4R inoperable cannot get sated except with very substantial, high-fat meals, and have a strong tendency to become obese. “
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The second generation of studies focused on very common genetic variants: thousands have been identified that influence the predisposition to obesity, but each has a very small effect. “Our study – continues Lotta – can perhaps be considered the progenitor of a third generation that aims to identify protective genetic variants, through large-scale sequencing”.
12 new genes associated with obesity
Exome sequencing allowed researchers to find rare genetic variants and understand their influence on body weight differences in hundreds of thousands of people. Although this index is an inaccurate measure of obesity, it has some advantages: in large populations it correlates with body fat percentage, is easily measurable, and varies little in the short term. In this study, 16 genes associated with body mass index were identified. Of these genes, four had already been associated with obesity, while 12 are “unpublished”. Most of these genes are expressed in the hypothalamus: again, that is, in a part of the nervous system that controls appetite and energy balance. And variants of the GPR75 gene, in particular, were found to have the greatest effect on body mass index.
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The variant of the GPR75 gene that halves the risk of being obese
“Having included both obese people and people who are thin or of normal weight, we have been able to identify rare genetic variants that protect carriers from obesity,” explains Lotta: “In particular, we have identified variants that inactivate a copy of GPR75. These variants are present in just over 3 people out of 10,000 and carriers have a halved risk of obesity compared to non-carriers of the same population ”. The researchers then studied the effects of these variants in mice subjected to a high-fat diet, proving their “protective” role and resistance to obesity, at least – for now – in these animals. Mice with a non-functional copy of the gene, in fact, gained less weight – gaining 44% less weight – than mice in the control group, showing better glycemic control and greater insulin sensitivity.
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According to the scientists, GPR75 could therefore be a “target” for new drugs. There are already two molecules capable of inactivating the receptors of this protein, but a new molecule is thought to be able to turn off the gene. “Obesity is one of the major health problems globally and has a strong hereditary component”, Lotta points out: “This is why we have prioritized this aspect in our research program. But we are using the same approach for several other diseases, to try to identify genetic variants present in the population that protect the carriers of these mutations ”.
“The principles of the discovery go beyond possible applications in weight control,” they write in a commentary in Science Giles S. H. Yeo e Stephen O’Rahilly of Cambridge University and Addenbrooke’s Hospital, confirming this view. According to the two scientists, large-scale exome sequencing increases our ability to understand the mechanisms of biology. It bypasses, in fact, two problems of classical Genome-Wide association studies: the rapid identification of the genes that cause an effect and the direction of this effect. And, in ongoing features such as obesity or hypertension, it also allows for the discovery of protective variants, as this study has shown.