L’obésité est une pathologie complexe multifactorielle considérée comme une maladie des centres régulateurs du poids. La contribution de la génétique est constante mais son impact est variable selon les situations allant des obésités génétiques de cause rare (environ 5 % des obésités) aux situations d’obésité dite polygénique (ou obésité commune) plus souvent rencontrées (95 % des cas). D’autres facteurs (déterminants précoces pré- et post-nataux, sociétaux ou psychologiques) interagissent toujours étroitement avec ces facteurs génétiques expliquant la grande variabilité du phénotype et la physiopathologie complexe. Un véritable continuum existe entre toutes ces situations via l’implication de variants génétiques plus ou moins rares situés dans des gènes codant pour des protéines clé de la régulation centrale de la prise alimentaire. Cette meilleure compréhension des mécanismes a permis de mieux préciser les phénotypes associés et d’aboutir depuis quelques années à des innovations thérapeutiques ciblant ces gènes-clé. Cette évolution permet d’envisager à moyen terme le développement d’une véritable médecine personnalisée dans l’obésité précoce associant des traitements médicamenteux ciblés selon l’anomalie génétique identifiée et/ou une prise en charge globale multidisciplinaire ciblée selon le phénotype du patient voire le recours à la chirurgie bariatrique selon les situations cliniques.

Obesity is a complex, multifactorial disease due to a dysfunction of the hypothalamic control of weight and food intake. The contribution of genetics is constant, but its impact is variable depending on the situations ranging from rare genetic obesities (around 5% of cases) to more frequently polygenic obesity (or common obesity) (95% of cases). Other factors as pre- and post-natal, societal or psychological determinants always interact closely with these genetic factors explaining the high variability of the phenotype and the complex pathophysiology. A true continuum exists between all these situations through the involvement of more or less rare genetic variants located in genes encoding key proteins in the central regulation of food intake. Rare forms of obesity are characterized by their common phenotype including a very early-onset severe obesity (BMI Z score greater than+3 SD early before the age of 3 years) with resistance to medical treatment, and major eating disorders characterized by difficulties in voluntary control of food intake. Central endocrine abnormalities such as hypogonadotropic hypogonadism or GH deficiency for example, and metabolic abnormalities due to abnormal adipose tissue distribution are also associated with variable degrees (Alström syndrome for example). Neuropsychological abnormalities are also present such as neurodevelopmental disorders (intellectual disability with variable intensity and/or adaptive development disorders which are part of many syndromes such as in Prader-Wili Syndrome; autism spectrum disorders (in SH2B1 or MYT1L deficiency for example), cognitive disorders with difficulties in emotional regulation (eg: Bardet-Biedl Syndrome or specific rare variants located on genes of the melanocortin pathway), behavioral or psychiatric disorders, sleep disorders and major hypothalamic dysfunctions (eg: Prader-Willi Syndrome, Smith Magenis syndrome). This better understanding of the mechanisms has made it possible to better precise the associated phenotypes and, recently, to lead to therapeutic innovations targeting these key genes. This evolution helps to quickly envisage the development of a real personalized medicine in early onset obesity using the combination of drug treatments targeted according to the identified genetic anomaly and/or a multidisciplinary global approach targeting the patient's phenotype or even the bariatric surgery in specific situations.