Addenbrookes Hospital, Cambridge, CB2 2QQ, United Kingdom
Caroline Brain and Stephen S. Nussey
St. Georges Hospital Medical School, London, SW17 ORE, United Kingdom
Proopiomelanocortin (POMC) is the precursor of a number of hormones and
neuropeptides. It is cleaved tissue-specifically to yield peptides with
diverse functions, such as adrenocorticotrophin (ACTH), , ß, and
-melanocyte stimulating hormone (MSH), ß-lipotrophin, and
ß-endorphin (1). The most clearly defined physiological role of these
peptides is the control of adrenal steroidogenesis by anterior
pituitary-derived ACTH, as well as skin pigmentation by
-MSH.
Evidence for a role of POMC gene products in the control of human
energy balance is accumulating rapidly. Thus, Krude et al.
reported two families in which mutations in the POMC gene result in
congenital ACTH deficiency with extreme early-onset obesity (2), and
two groups have just reported mutations in the melanocortin-4 receptor
(MC4R) that are associated with morbid obesity (3, 4). The MC4R is
highly expressed in the hypothalamus and binds
-MSH with high
affinity (5).
These human discoveries add to the substantial body of murine evidence for a key role of melanocortin signaling in energy homeostasis. This includes the obesity seen with MC4R "knock-out" (6), the inhibition of hypothalamic melanocortin signaling due to ectopic expression of Agouti protein (7), and transgenic overexpression of Agouti-related peptide (Agrp) (8). Thus, mechanisms leading to human and murine obesity include defects that affect the function and/or expression of POMC-derived ligands, their receptors, and their antagonists.
An additional molecular mechanism for defective melanocortin signaling leading to obesity may be impaired proteolytic processing of POMC to its effector hormones and neuropeptides. Thus, in fat/fat mice, obesity is associated with mutations of carboxypeptidase E and a failure to process POMC normally (9). Jackson et al. reported a woman with compound heterozygous mutations in prohormone convertase 1 (PC1), in whom marked impairment of POMC processing was associated with severe early-onset obesity (10). However, in both cases the specific linkage of impaired POMC processing to obesity is complicated by the widespread roles that PC1 and CPE have in propeptide processing. In this regard, we would like to report a novel form of human early-onset obesity, in which defective prohormone processing appears to be confined to POMC. The patient is a 9-yr-old caucasian female who is the second child of healthy, non consanguineous parents. Her early clinical and biochemical features, before development of obesity, have been described previously (11, 12). Briefly, she presented at 11 h of age with hypoglycemia associated with undetectable plasma cortisol and ACTH. Despite this, plasma POMC concentrations were markedly elevated and responded appropriately to corticotrophin releasing hormone and dexamethasone, suggesting a prohormone processing defect. However, the sequence of the POMC gene was normal. Unlike the fat/fat mouse and the PC1-defective human, the ratio of proinsulin to insulin in her plasma was also normal, suggesting that PC1 and CPE are intact because they are critical for proinsulin processing. The responses of serum glucagon to glucose and glucagon-like peptide 1 (GLP1) to a test meal were also normal.
We have now established that her PC1 genomic sequence is normal in all
14 exons, the exon/intron boundaries, and the promoter region.
Strikingly, despite only physiological cortisol replacement (mean daily
cortisol dose from age 29 yr was 14.8 mg/m2) and normal
linear growth (10th centile height at age 2 yr,
50th at 5.5 yr, and 75th at age 9 yr), marked
obesity has developed (Fig. 1).She displays hyperphagia and food-seeking behavior such that access to
food has to be restricted, and efforts to implement stringent dietary
control (Fig. 1
, arrows) result in marked social
difficulties.
|
In conclusion, the early-onset obesity seen in this child is further evidence for the role of impaired prohormone processing in mammalian obesity. Additionally, the specificity of the processing defect provides evidence for the importance of melanocortin signaling in the control of energy balance in man.
Footnotes
Received October 6, 1998. Address correspondence to: Robert S. Jackson, Department of Clinical Biochemistry, Box 232, Addenbrookes Hospital, Cambridge, CB2 2QQ, United Kingdom.
References