A newly discovered genetic variant predisposes people to become slim

Researchers from the Spanish National Cancer Research Centre and the IMDEA Food Institute discovered that persons who have a specific form of a gene involved in cell feeding develop less fat.

How much effect do our genes have on our body weight? Previous research suggests that genetics influence roughly 20% of body weight in the general population. This suggests that lifestyle variables such as nutrition and exercise have a substantial influence, but genetics also play a role, according to Nerea Deleyto-Seldas, a researcher at the Spanish National Cancer Research Centre (CNIO).

Nearly 100 genetic variations have been identified that moderately enhance the risk of having a high BMI. A new genetic variation has been discovered by the Spanish National Cancer Research Centre (CNIO) and the IMDEA Food Institute. The work was co-authored by Nerea Deleyto-Seldas of the CNIO and Lara P. Fernandez of the IMDEA Food Institute and published in the journal Genome Biology.

Genetic variations are slightly altered forms of a gene that seldom cause noticeable alterations in the body. However, this specific mutation has an effect on the amount of fat the body stores, and the authors of the current study found that it is especially common in Europe. It is believed that over 60% of the European population is infected.

"The result represents a step advance in our understanding of the genetic components of obesity," says Alejo Efeyan, leader of the CNIO's Metabolism and Cell Signalling Group. The IMDEA Food Institute's director, Ana Ramirez de Molina, feels that "a thorough understanding of the role of the cellular nutrient-sensing system in obesity may have consequences for the development and deployment of tailored methods in the prevention and treatment of obesity."

790 participants' genetic and clinical data

Obesity and overweight are described as an abnormal or excessive buildup of fat that has a negative impact on health. A team from the IMDEA Food Institute collected genetic material and data from 790 healthy volunteers, including body weight, BMI, total and visceral fat, muscle mass, waist, and hip circumferences, among other things, to find genetic variants that influence the phenomenon and the associated metabolic alterations.

Researchers investigated the probable connections of these characteristics with 48 genetic variations chosen for their potential functional significance. The researchers discovered a "significant association between one of these variations in the FNIP2 gene and several of these obesity-related indicators," according to the study, which was just published in the scientific journal Genome Biology.

Animal models are used to demonstrate

The CNIO team then investigated the impact of this mutation in mice that had been genetically modified to express it. "The researchers discovered that mice with this variation, which is related to leanness in humans, have between 10% and 15% less fat than their non-carrier counterparts," Efeyan continues.

In humans, the effect of this variation cannot be separated from the numerous other genetic and environmental factors that determine physical constitution, making it hard to assess the degree of its effect properly. However, considering that genetics have a 20% effect on obesity, the contribution of the newly found variation must be minimal.

As a result, researchers employ phrases such as inclination or tendency: "It is not at all the case that persons with this genetic mutation may consume without becoming obese," Efeyan emphasizes.

The animals that were genetically changed for this investigation had no additional changes or differences. "The findings in mice are particularly interesting since many of these studies are normally confined to revealing connections in the human population; in this article, we show that altering a single letter in the complete mouse genome mimics what we saw in the human variation," Efeyan explains.

Considering what the cell 'eats,'

This variation is found in a gene that is involved in a signalling system that informs the cell about available nutrients. It is now necessary to investigate why a little genetic alteration impacts the predisposition to be lean.

Future plans include "better understanding the molecular foundation of the impacts of this genetic mutation, i.e. what is occurring biochemically to the cell," according to Nerea Deleyto. "We need to enhance the genetic tools to determine whether the functional ramifications of this mutation are essential in the organism, such as during fat growth," she emphasizes.

The discovery raises further concerns for other fields of study, such as what evolutionary factors favored the selection of this variation and when it happened.

Note: However, the researchers emphasize that this finding does not imply that persons with this genetic mutation may overeat without gaining weight. The research offers a significant breakthrough in our knowledge of the genetic variables that contribute to obesity and may lead to novel therapies for the illness.

Reference: Fernández, L.P., Deleyto-Seldas, N., Colmenarejo, G. et al. Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region. Genome Biol 23, 230 (2022). https://doi.org/10.1186/s13059-022-02798-5