ABSTRACT
Genetic forms of obesity are primarily linked to alteration in energy homeostasis (i.e., food intake and energy expenditure) involving hypothalamic neuronal networks. The leptin–melanocortin pathway, located within hypothalamic nuclei, plays a major role in regulating energy balance in humans. Disruption in this pathway is associated with severe early-onset obesity, due to impairment in hunger and satiety, leading to eating disorders such as hyperphagia, food impulsivity, and food-seeking behavior. Carriers of genetic variants in the leptin–melanocortin pathway can also display neurodevelopmental disorders, sensory impairments, endocrine deficiencies, and/or organ malformations. The genes initially described and involved in these genetic forms of obesity were those coding for leptin (LEP), leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PC1), and melanocortin 4 receptor (MC4R). Recently, with the widespread use of powerful genetic sequencing tools, new genes coding for proteins located in the hypothalamic leptin–melanocortin pathway or regulating it have been identified. Some molecular mechanisms linking single-gene defects to obesity have been deciphered using in vitro and in vivo models. This has allowed innovative therapies to emerge. In patients with severe early-onset obesity, the implementation of genetic diagnosis in clinical practice now enables personalized medicine including comprehensive multidisciplinary and coordinated care.
