Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Dec;57(12):3267-72.
doi: 10.2337/db08-0577. Epub 2008 Oct 3.

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

Jonathan Krakoff  1 , Lijun Ma, Sayuko Kobes, William C Knowler, Robert L Hanson, Clifton Bogardus, Leslie J Baier
Affiliations

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

Jonathan Krakoff et al. Diabetes. 2008 Dec.

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 = 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 approximately 140 kcal/day), indicating that lower energy expenditure was a component of the increased adiposity.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
A: 24-h energy expenditure (EE) versus FFM. B: Sleep energy expenditure versus FFM. C: RMR versus FFM. □, neither variant; ▴, NT100 variant; •, R165Q variant.
See this image and copyright information in PMC

References

    1. Barsh GS, Farooqi IS, O’Rahilly S: Genetics of body-weight regulation. Nature 404 :644 –651,2000 - PubMed
    1. Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O’Rahilly S: Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 106 :271 –279,2000 - PMC - PubMed
    1. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S: Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348 :1085 –1095,2003 - PubMed
    1. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F: Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88 :131 –141,1997 - PubMed
    1. Ste ML, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD: A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci U S A 97 :12339 –12344,2000 - PMC - PubMed

Publication types

MeSH terms