Precision medicine in childhood obesities

Abstract

Obesity is currently one of the most common consultations in pediatrics due to its high prevalence rate in our environment. Even though an impaired balance between caloric intake and energy expenditure underlies the excessive accumulation of adipose tissue in most cases of childhood and adolescent obesity, there is a high interindividual variability in the susceptibility to develop obesity, which is based largely on each person’s singular genetic background. Advances in our understanding of the latter arise from the progressive unravelling of the pathophysiological bases of the mechanisms involved in the control of appetite, satiety, and energy expenditure. An important body of evidence in this field has derived from the study of an increasing number of cases of obesity with proven genetic (either syndromic or not), endocrinological or secondary etiology. Consequently, we now need to speak in term of «childhood obesities» when referring to the common phenotypic trait of excessive adipose tissue accumulation as the underlying pathophysiological bases are widely different between subjects; thus, individualized diagnostic and management approaches both, for obesity itself as for its associated comorbidities are required. Furthermore, the advances made in identifying patients with monogenic diseases cosegregating with the phenotype of obesity have considerably increased the modern pathophysiological bases of obesity. Therefore, it is imperative to individualize the diagnostic strategy, thus leading to a relevant change in the therapeutic approach. In fact, the results obtained by using the analog of melanocortin, setmelanotide, in patients with POMC (proopiomelanocortin), LEPR (leptin receptor) and PCSK1 (proprotein concertase subtilisin-kexin type 1) deficiency, and more recently studies of the structure and architecture of the MC4R (melanocortin receptor number 4), may allow a more precise analysis of the effects of the loss-of-function mutations in MC4R associated to obesity, as well as structural prediction of their responsiveness to setmelanotide, leading to a personalized therapy based on precision medicine.