For a long time, obesity was explained almost exclusively by an imbalance between calories consumed and calories expended. Today, scientific research shows that the reality is far more complex.
While diet and physical activity play a central role, our genes and internal biology strongly influence our relationship with weight : appetite, fat storage, energy expenditure, responses to treatment and the ability to maintain weight loss.
Recent advances in the genetics of obesity invite a change in perspective. Rather than blaming people who are overweight, the aim is to understand the biological mechanisms involved and offer more appropriate prevention and care strategies.
A disease at the intersection of genes and the environment
Obesity is a multifactorial condition resulting from the interaction between genetic, environmental and behavioural factors. Researchers distinguish several levels of genetic contribution.
Monogenic obesity: rare but powerful mutations
In around 0.5 to 1% of cases, a mutation in a single gene can be enough to cause severe obesity, often from childhood. These forms of monogenic obesity are rare, but highly informative: they demonstrate that disrupting a single component of weight-regulation circuits can profoundly disturb energy balance.
Syndromic obesity: complex clinical presentations
Around 4% of obesity cases are described as syndromic. They result from rare mutations associated with multiple clinical manifestations, such as morphological abnormalities or neurodevelopmental disorders. These forms usually begin early, are severe and require specialist care.
Polygenic obesity: the most common situation
In almost 95% of cases, obesity is polygenic. It results from the cumulative effect of hundreds of genetic variants, each with a small individual effect, but whose combination can significantly increase the risk of weight gain.
Large genetic studies (GWAS) have identified many regions of the genome associated with BMI, fat distribution and waist circumference. These data now make it possible to develop polygenic risk scores, indicating whether a person is more or less vulnerable to obesity in a comparable environment.
A high genetic score is not destiny. It does not determine obesity, but lowers the threshold at which the environment — diet, inactivity, stress and sleep — can upset the balance.
A "metabolic memory" of obesity written into tissues
A key concept highlighted by recent studies is the metabolic memory of adipose tissue.
Even after significant weight loss, adipose tissue does not fully return to its initial state.
Researchers observe lasting changes in:
gene expression,
chromatin organisation,
epigenetic markers, such as DNA methylation.
This biological memory could explain:
the tendency to regain weight after dieting,
the difficulty of maintaining weight loss in the long term,
persistent metabolic disturbances, including inflammation and insulin resistance.
These findings do not call into question the effectiveness of lifestyle changes or treatments, but help us understand why the body sometimes resists weight loss and why some patients need more intensive, sustained support.
The brain: orchestrating appetite and satiety
Obesity is not simply an excess of adipose tissue. It also involves changes in the functioning of brain circuits that regulate:
hunger and satiety,
food reward,
motivation for physical activity.
Some genetic variants affect genes involved in:
the synapse, the communication point between neurons,
neuronal cilia, structures essential for receiving hormonal signals.
These changes can:
increase hunger,
reduce satiety,
increase the appeal of foods high in sugar and fat.
In the same environment, two individuals may therefore perceive very different internal signals. What is easy for one person may be a daily struggle for another.
Genetic diversity and risk scores: a broader view of obesity
The first large genetic studies mainly involved populations of European ancestry. Recent work highlights the importance of incorporating greater ancestral diversity in order to:
identify new genes and specific variants,
improve the accuracy of risk scores,
avoid widening health inequalities.
These approaches have already identified new mechanisms involving adipose tissue, the extracellular matrix and circadian rhythms, opening new avenues for prevention and treatment.
Towards precision medicine for obesity
Genetic data are beginning to transform clinical practice. Researchers are exploring, in particular:
the influence of genetic variants on responses to drugs acting on gut hormones (GLP-1, GIP),
the use of risk scores to identify high-risk individuals earlier,
adjusting the intensity of interventions, including lifestyle changes, pharmacotherapy and bariatric surgery,
monitoring people most at risk of regaining weight.
Care is moving towards personalised pathways that take into account:
genetic profile,
weight and metabolic history,
psychological and social context,
lifestyle.
Genetics does not replace the environment, but helps us better understand individual responses. The challenge in the coming years will be to combine genetic, clinical and behavioural data to improve the prevention and treatment of obesity.
Learn about the genetics of obesity with ADNAcademy
By incorporating advances in the genetics and epidemiology of obesity, ADNAcademy supports healthcare professionals towards more preventive, personalised practice informed by current science.
Our courses help you understand the biological mechanisms of weight and adapt care strategies to each patient’s profile.