The first-order neuronal targets of leptin action in the brain are anorectic (reducing food intake) pro-opiomelanocortin (POMC) and orexigenic (increasing food intake) neuropeptide-Y/Agouti-related protein (NPY/AgRP) neurons in the hypothalamic arcuate nucleus, where the signalling isoform of the leptin receptor is highly expressed (Schwartz et al., 2000). Forty percent of POMC neurons in the arcuate nucleus express the mRNA for the long form of the leptin receptor and POMC expression is regulated positively by leptin. POMC is sequentially cleaved by prohormone convertases to yield peptides including a-MSH that have been shown to play a role in feeding behavior.
Two unrelated obese German children with homozygous or compound heterozygous mutations in POMC have been reported (Krude et al., 1998). These children were hyperphagic, developing early-onset obesity as a result of impaired melanocortin signalling in the hypothalamus. They presented in neonatal life with adrenal crisis due to ACTH deficiency (POMC is a precursor of ACTH in the pituitary) and had pale skin and red hair due to the lack of MSH function at melano-cortin 1 receptors in the skin (Krude et al., 1998). A number of groups have identified a heterozygous missense mutation (Arg236Gly) in POMC that disrupts the dibasic amino acid processing site between p-MSH and p-endorphin, resulting in an aberrant p-MSH/p-endorphin fusion peptide which binds to MC4R with an affinity identical to that of a- and p-MSH but has a markedly reduced ability to activate the receptor (Challis et al., 2002). Thus this cleavage site mutation in POMC may confer susceptibility to obesity through a novel molecular mechanism.
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