Inactivation of the melanocortin-4 receptor (MC4-R) by gene-targeting results in mice that develop maturity-onset obesity, hyperinsulinemia, and hyperglycemia. These phenotypes resemble common forms of human obesity, which are late-onset and frequently accompanied by NIDDM. It is not clear whether sequence variation of the MC4-R gene contributes to obesity in humans. Therefore, we examined the human MC4-R gene polymorphism in 190 individuals ascertained on obesity status. Three allelic variants were identified, including two novel ones, Thr112Met and Ile137Thr. To analyze possible functional alterations, the variants were cloned and expressed in vitro and compared with the wild-type receptor. One of the novel variants, Ile137Thr, identified in an extremely obese proband (BMI 57), was found to be severely impaired in ligand binding and signaling, raising the possibility that it may contribute to development of obesity. Furthermore, our results also suggest that sequence polymorphism in the MC4-R coding region is unlikely to be a common cause of obesity in the population studied, given the low frequency of functionally significant mutations.

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This study extended initial observations that indicated the potential of dualphoton absorptiometry (DPA) to measure total-body bone mineral (TBBM) and fat in vivo. DPA-derived TBBM and fat were compared with established methods in 13 subjects (aged 24-94 y) who underwent measurement of body density (Db), total-body water (TBW), potassium (TBK), calcium (TBCa, delayed-gamma neutron activation), and nitrogen (prompt-gamma neutron activation). TBBM was highly correlated with TBCa (r = 0.95, p less than 0.001) and the slope of TBCa vs TBBM (0.34) was similar to Ca content of ashed skeleton (0.34-0.38). DPA-measured fat (means +/- SD, 16.7 +/- 4.9 kg) correlated significantly (r = 0.79-0.94; p less than 0.01-0.001) with fat established by Db (16.3 +/- 5.4 kg), TBW (16.0 +/- 4.3 kg), TBK (17.7 +/- 4.6 kg), combined TBW-neutron activation (17.6 +/- 5.9 kg), and means of all four methods (16.9 +/- 4.8 kg). DPA thus offers a new opportunity to study human skeleton in vivo and to quantify fat by a method independent from the classical assumption that bone represents a fixed fraction of fat-free body mass.