Lessons from extreme human obesity: monogenic disorders

Abstract

Human obesity has a strong genetic component. Most genes that influence an individual's predisposition to gain weight are not yet known. However, the study of extreme human obesity caused by single gene defects has provided a glimpse into the long-term regulation of body weight. These monogenic obesity disorders have confirmed that the hypothalamic leptin-melanocortin system is critical for energy balance in humans, because disruption of these pathways causes the most severe obesity phenotypes. Approximately 20 different genes and at least three different mechanisms have been implicated in monogenic causes of obesity; however, they account for fewer than 5% of all severe obesity cases. This finding suggests that the genetic basis for human obesity is likely to be extremely heterogeneous, with contributions from numerous genes acting by various, yet undiscovered, molecular mechanisms.

Figure 1. Leptin-Melanocortin system of energy balance

PVN paraventricular nucleus of the hypothalamus. ARC arcuate nucleus of the hypothalamus. LepR leptin receptor. NPY neuropeptide Y. AgRP agouti-related peptide. POMC proopiomelanocortin. α-MSH α-melanocyte stimulating hormone. MC4R melanocortin 4 receptor. Information about the body’s energy stores is conveyed to the brain by hormones such as leptin. Leptin is secreted by adipocytes in proportion to the body’s fat mass. Leptin binds to its receptors on two populations of neurons in the arcuate nucleus of the hypothalamus: the orexigenic AgRP/NPY-expressing neurons, and the anorexigenic POMC-expressing neurons. These two groups of neurons have projections to the paraventricular nucleus of the hypothalamus, as well as to other regions of the brain. The PVN has a dense neuronal population that expresses MC4R. When leptin binds its receptors on POMC neurons, α-MSH, a cleavage product of the POMC transcript, is released. Activation of MC4R in the PVN by α-MSH relays a satiety signal and causes a decrease in food intake. AgRP is an antagonist of MC4R, and competes with α-MSH to bind MC4R. Binding of AgRP to MC4R leads to increased food intake. Leptin activates POMC neurons and inhibits AgRP neurons. Therefore, by activating its receptors on these two neuronal populations, leptin acts in a concerted way to increase MC4R activation by α-MSH and decrease its antagonism by AgRP, to cause a decrease in food intake. Mutations in genes with critical roles in the Leptin-Melanocortin system cause early-onset, severe obesity. Autosomal recessive mutations in leptin, leptin receptor, POMC and PC1/3, and autosomal dominant MC4R mutations have been described.

Figure 2. Processing of POMC

POMC proopiomelanocortin. ACTH adrenocorticotropic hormone. PC1/3 prohormone convertase 1/3. PC2 prohormone convertase 2. α-, β- and γ-MSH α-, β- and γ-melanocyte stimulating hormone. POMC is processed by PC1/3 and PC2 into 5 biologically active proteins. In the corticotropes of the anterior pituitary, PC1/3 is expressed, but PC2 is not. Therefore, ACTH is the only biologically active POMC-derived peptide synthesized in the anterior pituitary. Both PC1/3 and PC2 are expressed in the melanotropes of the hypothalamus and skin. Thus, POMC is sequentially processed into α-, β- and γ-MSH and β-endorphin in these tissues. The phenotype of POMC deficiency is explained by the tissue-specific lack of these cleavage products.