Lower Metabolic Rate in Individuals Heterozygous for Either a Frameshift or a Functional Missense MC4R Variant

Abstract

Objectives: Humans with functional variants in the melanocortin 4 receptor (MC4R) are obese, hyperphagic and hyperinsulinemic but have been reported to have no difference in energy expenditure (EE).

Research Design and Methods: We investigated the association of two MC4R variants, Arg165Gln (R165Q) and A insertion at nucleotide 100 (NT100) with adiposity in 3074 full-heritage Pima Indians, a subset of whom had metabolic measures including 24 hour EE (24h-EE;N=252) and resting metabolic rate (RMR;N=364).

Results: Among the 3074 subjects,43 were heterozygous for R165Q and 14 for NT100 (frequency = 0.007 and 0.002). Mean (± SD) body mass index was higher among subjects with R165Q (39.3 ± 8.6 kg/m²) 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). 24h-EE (4 with NT100; 3 with R165Q) or RMR (6 with NT100; 2 with R165Q) was lower in heterozygous subjects, but only met statistical significance when heterozygous subjects were combined and compared to subjects without either variant (least square means (95% confidence limits); 2163 (2035–2291) vs. 2307 (2285–2328) kcals/24h, p=0.03 for 24h-EE and 1617 (1499–1734) vs. 1754 (1736–1772) kcals/24h, 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 EE (by ∼ 140 kcal/day), indicating lower EE as a component of the increased adiposity.