ABSTRACT
Rare genetic disorders can serve as tools for understanding normal physiology, including the complex regulation of human energy balance, which is so intricately fine-tuned that typical fluctuations in body weight are small and gradual despite vastly changing energy intake and expenditure on a day-to-day basis. Elucidating the mechanism by which genetic defects associated with hyperphagia and obesity exert their effects has expanded the understanding of body weight regulation and revealed potential targets for treating not only the rare forms of genetic obesity but also common variants in the same genes, which may contribute to the general population variance in body mass index. Therapies, such as metreleptin and setmelanotide, targeting specific defects within the leptin signaling pathway, have yielded effective treatments for obesity caused by insufficiencies of leptin, leptin receptor, proopiomelanocortin, and proprotein convertase subtilisin/kexin type 1. Syndromic conditions associated with obesity, including Prader-Willi syndrome and ciliopathy disorders, such as Bardet-Biedl and Alström syndromes, appear to have deficits in energy homeostasis that also converge upon the leptin pathway, thereby offering precision medicine targets that are under investigation for use in combination with nutrition, physical activity, and other lifestyle interventions for weight management in these rare disorders.
