Mice Are Not Men

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Science  03 Mar 2006:
Vol. 311, Issue 5765, pp. 1215
DOI: 10.1126/science.311.5765.1215c

Pro-opiomelanocortin (POMC) undergoes posttranslational processing to yield a bunch of physiologically active peptides. In the hypothalamus, POMC is a precursor to the melanocortins (α-MSH, β-MSH, and γ-MSH). Humans and mice lacking functional POMC or MC4R (melanocortin-4 receptor, which is activated by α- and β-MSH) become obese; because rodents cannot synthesize β-MSH, this effect has been attributed to α-MSH. Biebermann et al. find that a severely obese child has a mutant form of β-MSH in which a cysteine has been substituted for a tyrosine, a mutation also present in obese family members. Restriction enzyme analysis of 722 obese and 1270 non-obese children and adolescents uncovered the mutation in 2 obese individuals and none of the controls. Lee et al. discovered the same β-MSH variant in 5 of 538 unrelated severely obese children and 1 of 300 non-obese adults and found that the mutation segregated with obesity in family members. Both groups observe that the mutant form showed substantially reduced binding to human MC4R and conclude that, unlike in rodents, β-MSH is important in regulating energy balance and body weight in humans. — EMA

Cell Metab. 3, 141; 135 (2006).

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