| Abstrakt: |
The hypothalamus plays a major role in the long-term regulation of body weight in humans. Within the hypothalamus, the leptin–melanocortin system is critical for energy balance, as animal and human studies have shown that disruption of this pathway, which senses peripheral energy stores and signals satiety, leads to the most severe forms of human obesity. The monogenic causes of obesity identified so far in this pathway are very heterogeneous and account for less than 5% of severe obesity. The genetic basis of the remaining 95% of obesity is likely to be even more heterogeneous and polygenic. The melanocortin 4-receptor (MC4R) is the most specialized molecule for body weight maintenance within this system as the clinical phenotype of MC4R deficiency is limited to obesity. Indeed, heterozygous MC4R mutations are the most common cause of monogenic obesity. In addition, novel mechanisms are emerging as important for pathogenicity of obesity, such as abnormal hypothalamic development, alterations in neuronal plasticity, and dysfunction of the primary cilium. This chapter focuses on obesity caused by mutations in genes that have a physiologic role in the hypothalamic leptin–melanocortin system of energy balance. [ABSTRACT FROM AUTHOR] |
