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

Abstract

OBJECTIVE-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.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 ϭ 252) and resting metabolic rate (RMR) (n ϭ 364).RESULTS-Among the 3,074 subjects, 43 were heterozygous for R165Q and 14 for NT100 (frequency ϭ 0.007 and 0.002). Mean (Ϯ SD) BMI was higher among subjects with R165Q (39.3 Ϯ 8.6 kg/m 2 ) or NT100 (41.2 Ϯ 7.8) than subjects without either variant (37.1 Ϯ 8.4) (P ϭ 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 ϭ 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 ϭ 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-PimaIndians heterozygous for R165Q or NT100 in MC4R have higher BMIs and lower energy expenditure (by ϳ140 kcal/day), indicating that lower energy expenditure was a component of the increased adiposity. Diabetes 57: 3267-3272, 2008 E nvironment plays an important role in the development of obesity, but considerable evidence exists for a genetic contribution to body weight (1). Several genes including the melanocortin 4 receptor (MC4R) located on chromosome 18q22 have been identified as monogenic causes of obesity in humans (2). Many of the identified variants in MC4R lead to partial or complete loss of receptor activity (3). Mice lacking MC4R are obese, are hyperinsulinemic, have increased food intake (4), and have lower energy expenditure (5). Humans with MC4R mutations are obese, are hyperinsulinemic, and have increased food intake, but no difference in energy expenditure has been reported (3).The Pima Indians of southern Arizona have a high prevalence of obesity (6). Sequencing of the coding region of MC4R in 300 severely obese and 126 nonobese Pima Indians identified 10 individuals (all obese) heterozygous for a previously characterized G-to-A substitution at nucleotide 165 (R165Q) that leads to partial inactivation of MC4R (3). Three additional individuals (all obese) were found to be heterozygous for a novel single-base insertion (A) at nucleotide 100 (NT100) that predicts a frameshift resulting in a premature STOP (TGA) at codon 37 (7). A premature STOP codon at this position would produce a truncated protein lacking critical lig...

Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity

“…Further analyses of these individuals demonstrate that the defects influence appetite and satiety resulting in increased food intake. In contrast, little or no effect is observed on energy expenditure, with MC4R mutation patients being the exception and showing a small but significant reduction in metabolic rate (264).…”

Inhibition of the central melanocortin system decreases brown adipose tissue activity

“…Additionally, chronic icv SHU9119 treatment in rats increases the RER ( 8 ), indicative of reduced lipid utilization. Interestingly, variants near and in the MC4R gene in humans are associated not only with an increased RER ( 8 ), but also with reduced total energy expenditure (EE) ( 11,12 ), underscoring the importance of the melanocortin system in the regulation of EE.…”

Functional body composition: insights into the regulation of energy metabolism and some clinical applications

“…This variance remains to be explained. Adjusted REE was moderately heritable (i.e., B0.30; Bogardus et al, 1986;Bosy-Westphal et al, 2008a, b), but up to now, there is no clear evidence for specific genes adding to the interindividual variance in REE (Krakoff et al, 2008). In future, traits defined by measures of functional body composition (e.g., REE-FFM changes with both underfeeding and overfeeding) will provide functional evidence relating genetic variants.…”