Further evidence for the role of the melanocortin system in the regulation of body weight in humans comes from the description of a 47-year-old woman with severe childhood obesity, abnormal glucose homeostasis, very low plasma insulin but elevated levels of proinsulin, hypogonadotropic hypogonadism and hypocortisolemia associated with elevated levels of POMC (O'Rahilly et al., 1995). This subject was found to be a compound heterozygote for mutations in prohormone conver-tase 1, which cleaves prohormones at pairs of basic amino acids, leaving C-terminal basic residues which are then excised by carboxypeptidase E (CPE) (Jackson et al., 1997). We have also recently identified a child with severe, early-onset obesity who was a compound heterozygote for complete loss of function mutations in PC1 (Jackson et al., 2003). Although failure to cleave POMC is a likely mechanism for the obesity in these patients, PC1 cleaves a number of other neuropeptides in the hypothalamus, such as glucagon-like-peptide 1, which may influence feeding behaviour. Intriguingly, this second patient suffered from severe small intestinal absorptive dysfunction as well as the characteristic severe early-onset obesity, impaired prohormone processing and hypocorti-solemia. We hypothesized that the small intestinal dysfunction seen in this patient, and to a lesser extent in the first patient we described, may be the result of a failure of maturation of propeptides within the enteroendocrine cells and nerves that express PC1 throughout the gut. The finding of elevated levels of progastrin and proglucagon provided in vivo evidence that, indeed, prohormone processing in enteroendocrine cells was abnormal.
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