Brain reward and addiction mechanisms involved in genes for common obesity

The research team of Dr Amélie Bonnefond, within the “Integrative genomics and modeling of metabolic diseases” laboratory of Prof. Philippe Froguel (Institut Pasteur de Lille / University of Lille / CNRS), has just demonstrated that the genes of obesity common are involved in addiction and brain reward mechanisms and not in the regulation of hunger. This discovery was made possible thanks to the development of a new method to determine with certainty where in the human body the genes of common obesity were most expressed (presence of their specific RNA) and therefore where they exerted their “obesogenic” effect. Published in the International Journal of Obesity, this study paves the way for better management of so-called common obesity.

Obesity has become a global scourge affecting both rural and urban areas in developed and poorer countries as much or more. Excess weight is now the most important risk factor for early cardiovascular and cancer-related mortality. However, the origin of obesity remains a mystery. Although “obesogenic” environmental factors are very important at the population level, genetic factors account for 70% of the variable individual response to these exogenous factors. Since the 1990s, the work of Professor Philippe Froguel‘s team in Lille has demonstrated the importance of monogenic forms of childhood obesity, which affect between 5 and 50% of severely obese people, depending on the country. All these genes without exception control the processes of satiety and patients mutated for these genes have an unregulated appetite. They eat too much and therefore gain weight from an early age. Very different is common obesity, whose very polygenic origin was established in 2007 by the research team: currently so nearly 400 genes contribute in a modest way to the risk of obesity, we still do not know by what mechanisms they lead to overweight.

Dr Amélie Bonnefond‘s team, in Professor Philippe Froguel‘s laboratory, has thus developed a new method to determine with certainty where in the human body the genes for common obesity were most expressed (presence of their RNA specific) and therefore where they exerted their “obesogenic” effect. Indeed, while DNA is the same in all cells of a person, genes are expressed differently from cell to cell in different organs. The Lille study shows that most genes for common obesity are expressed preferentially in the brain and not in tissues that consume or store energy such as muscle and adipose tissue. Common obesity is therefore not a disease linked to a deficit in calorie expenditure but to excess food intake, the origin of which remains to be determined. The surprise of this study is the absence of preferential expression of the d genes. obesity common in the part of the brain that controls hunger ie the hypothalamus. However, an enrichment of these genes is found in two regions of the brain that are involved in reward and addiction mechanisms, the substantia nigra and the insula. In addition, the most important common obesity genes such as the FTO gene discovered in 2007 by the Lille team are those that are most expressed in these two particular regions of the brain.

It is well known that most obese people are no more hungry than people of normal weight but find it difficult to manage their eating behavior, especially when under stress or upset. One theory postulates that certain foods, especially sugars, are as addictive as hard drugs making obese people “addicted” to food, the excess intake of which would provide them with temporary well-being (reward mechanism). This has mainly been proven in animals. This work is the first biological demonstration in humans of the essentially behavioral nature of the genetic predisposition to common obesity.

While the interest of genetic scores predicting common obesity from birth has just been proposed, the Lille work paves the way for a policy of prevention and management of behavioral overweight (and not based on simply restrictive diets that make obese people even more addictive): managing stress better, avoiding getting into or out of food addiction situations is probably more effective in the fight against obesity.

Sources: The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward
Fatou K Ndiaye, Marlène Huyvaert, Ana Ortalli, Mickaël Canouil, Cécile Lecoeur, Marie Verbanck, Stéphane Lobbens, Amna Khamis, Lorella Marselli, Piero Marchetti, Julie Kerr-Conte, François Pattou, Michel Marre, Ronan Roussel, Beverley Balkau, Philippe Froguel & Amélie Bonnefond