Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant

Abstract

OBJECTIVE-Humans with functional variants in the melano-cortin 4 receptor (MC4R) are obese, hyperphagic, and hyperin-sulinemic but have been reported to have no difference in energy expenditure. RESEARCH DESIGN AND METHODS-We investigated the association of two MC4R variants, Arg165Gln (R165Q) and A insertion at nucleotide 100 (NT100), with adiposity in 3,074 full-heritage Pima Indians, a subset of whom had metabolic measures including 24-h energy expenditure (n= 252) and resting metabolic rate (RMR) (n=364). RESULTS-Among the 3,074 subjects, 43 were heterozygous for R165Q and 14 for NT100 (frequency=0.007 and 0.002). Mean (± SD) BMI was higher among subjects with R165Q (39.3 ±8.6 kg/m 2) or NT100 (41.2 ±7.8) than subjects without either variant (37.1±8.4) (P=0.04 and 0.02, adjusted for age, sex, and birth year and accounting for family membership). The 24-h energy expenditure (four with NT100; three with R165Q) or RMR (six with NT100; two with R165Q) was lower in heterozygous subjects but only met statistical significance when heterozygous subjects were combined and compared with subjects without either variant: least-squares means, 2,163 kcal/24 h (95% CI 2,035-2,291) vs. 2,307 kcal/24 h (2,285-2,328), P=0.03 for 24-h energy expenditure, and 1,617 kcal/24 h (1,499-1,734) vs. 1,754 kcal/24 h (1,736-1,772), P = 0.02 for RMR; adjusted for age, sex, fat-free mass, and fat mass). For RMR, this difference persisted, even after accounting for family membership. CONCLUSIONS-Pima Indians heterozygous for R165Q or NT100 in MC4R have higher BMIs and lower energy expenditure (by ∼40 kcal/day), indicating that lower energy expenditure was a component of the increased adiposity. © 2008 by the American Diabetes Association.