The functional loss of both alleles of the human pro-opiomelanocortin (POMC) gene leads to a very rare syndrome of hypoadrenalism, red hair and early-onset obesity. In order to examine whether more subtle genetic variants in POMC might contribute to early-onset obesity, the coding region of the gene was sequenced in 262 Caucasian subjects with a history of severe obesity from childhood. Two children were found to be heterozygous for a missense mutation, R236G, which disrupts the dibasic cleavage site between beta melanocyte-stimulating hormone (beta-MSH) and beta-endorphin. Beta-TC3 cells transfected with the mutant POMC cDNA produced a mutant beta-MSH/beta-endorphin fusion protein. This fusion protein bound to the human melanocortin-4 receptor (hMC4R) with an affinity similar to its natural ligands, but had a markedly reduced ability to activate the receptor. This variant co-segregated with early-onset obesity over three generations in one family and was absent in 412 normal weight UK Caucasian controls. Combining the results in UK Caucasians with a new case-control study in French subjects and three previously published reports, mutations disrupting this processing site were present in 0.88% of subjects with early-onset obesity and 0.22% of normal-weight controls. These results suggest that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signalling.

Proopiomelanocortin (POMC) undergoes extensive and tissue-specific posttranslational processing to yield a range of biologically active peptides. Historically, the most clearly defined roles of these peptides are in the control of adrenal steroidogenesis by corticotroph-derived ACTH and skin pigmentation by alphaMSH. However, a rapidly expanding body of work has established that POMC-derived peptides synthesized in neurons of the hypothalamus play a central role in the control of energy homeostasis. We review how inherited abnormalities in POMC synthesis and processing and defects in the action of POMC-derived peptides in both humans and mice have helped shape our current understanding of the importance of the melanocortin system in human energy balance.

Pathological fasting hypoglycemia in humans is usually explained by excessive circulating insulin or insulin-like molecules, or by inborn errors of metabolism impairing liver glucose production. We studied three unrelated children with unexplained, recurrent and severe fasting hypoglycemia and asymmetrical overgrowth. All were found to carry the same de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2, in two cases as heterozygotes and, in one case, in mosaic form. In heterologous cells, the mutant AKT2 was constitutively recruited to the plasma membrane, leading to insulin-independent activation of downstream signaling. This represents a novel mechanism of systemic metabolic disease, characterised by constitutive, cell-autonomous activation of signaling pathways normally controlled by insulin. Insulin promotes energy storage and growth through effects on glucose, lipid and amino acid metabolism, cell division and apoptosis. These are mediated by a transmembrane tyrosine kinase receptor that phosphorylates Insulin Receptor Substrate (IRS) and other adaptor proteins to initiate signaling events including, critically, activation of AKT serine/threonine kinases. Murine studies suggest that the AKT2 isoform is most closely linked to insulin's metabolic effects(1). Consistent with this, a loss-of-function mutation in AKT2 produces severe insulin resistance in humans(2).