OBESITY Of Mice, Men, and POMC

Proopiomelanocortin (POMC), which is expressed in several different tissues, undergoes posttranslational processing to yield various physiologically active peptide products. In the hypothalamus, POMC is a precursor to the melanocortins (-MSH, ß-MSH, and -MSH). Humans and mice lacking functional POMC or MC4R (melanocortin-4 receptor, a G-protein-coupled receptor activated by - and ß-MSH) become obese; because rodents cannot synthesize ß-MSH, this effect has been attributed to -MSH (see Leibel). Now, studies from two groups, Biebermann et al. and Lee et al., suggest that, in humans, ß-MSH plays a key role in regulating body weight. Biebermann et al. found that the POMC coding region of a severely obese child had a mutant form of ß-MSH in which a cysteine was substituted for a tyrosine, a mutation also present in obese family members. Restriction enzyme analysis of POMC in 722 obese and 1270 nonobese children and adolescents revealed the mutation in 2 obese individuals and no controls. Postmortem immunohistochemical analysis revealed neurons containing ß-MSH in the arcuate nucleus of human hypothalamus. Lee et al. discovered the same ß-MSH variant in 5 of 538 unrelated severely obese children and 1 of 300 nonobese adults and found that the mutation segregated with obesity in family members. NMR analysis indicated that the mutation altered the three-dimensional structure of ß-MSH. Both groups found that, compared with wild-type ß-MSH, the mutant form showed substantially reduced binding to human MC4R [expressed in Chinese hamster ovary (CHO)-K1 or human embryonic kidney 293 (HEK293) cells] and was far less effective at stimulating adenosine 3',5'-monophosphate (cAMP) production. Thus, both groups conclude that, unlike the situation in rodents, ß-MSH plays an important and previously unrecognized role in regulating human energy balance and body weight.

H. Biebermann, T. R. Castañeda, F. van Landeghem, A. von Deimling, F. Escher, G. Brabant, J. Hebebrand, A. Hinney, M. H. Tschöp, A. Grüters, H. Krude, A role for ß-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab. 3, 141-146 (2006). [PubMed]

Y. S. Lee, B. G. Challis, D. A. Thompson, G. S. H. Yeo, J. M. Keogh, M. E. Madonna, V. Wraight, M. Sims, V. Vatin, D. Meyre, J. Shield, C. Burren, Z. Ibrahim, T. Cheetham, P. Swift, A. Blackwood, C.-C. C. Hung, N. J. Wareham, P. Froguel, G. L. Millhauser, S. O'Rahilly, I. S. Farooqi, A POMC variant implicates ß-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab. 3, 135-140 (2006). [PubMed]

R. L. Leibel, The molecular genetics of the melanocortin pathway and energy homeostasis. Cell Metab. 3, 79-81 (2006). [PubMed]

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EDITORS' CHOICE
Metabolism
Regulating Glucose

Elizabeth M. Adler (18 September 2007)
Sci. STKE 2007 (404), tw337. [DOI: 10.1126/stke.4042007tw337]
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