MC3R links nutritional state to childhood growth and the timing of puberty

B. Y. H. Lam, A. Williamson, S. Finer, F. R. Day, J. A. Tadross, A. Gonçalves Soares, K. Wade, P. Sweeney, M. N. Bedenbaugh, D. T. Porter, A. Melvin, K. L. J. Ellacott, R. N. Lippert, S. Buller, J. Rosmaninho-Salgado, G. K. C. Dowsett, K. E. Ridley, Z. Xu, I. Cimino, D. Rimmington, K. Rainbow, K. Duckett, S. Holmqvist, A. Khan, X. Dai, E. G. Bochukova, R. C. Trembath, H. C. Martin, A. P. Coll, D. H. Rowitch, N. J. Wareham, D. A. van Heel, N. Timpson, R. B. Simerly, K. K. Ong, R. D. Cone, C. Langenberg, J. R. B. Perry, G. S. Yeo and S. O’Rahilly ()
Additional contact information
B. Y. H. Lam: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
A. Williamson: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
S. Finer: Wolfson Institute of Population Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
F. R. Day: MRC Epidemiology Unit, Wellcome–MRC Institute of Metabolic Science, University of Cambridge
J. A. Tadross: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
A. Gonçalves Soares: University of Bristol
K. Wade: University of Bristol
P. Sweeney: University of Michigan
M. N. Bedenbaugh: Vanderbilt University
D. T. Porter: University of Michigan
A. Melvin: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
K. L. J. Ellacott: University of Exeter Medical School
R. N. Lippert: German Institute of Human Nutrition
S. Buller: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
J. Rosmaninho-Salgado: Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra
G. K. C. Dowsett: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
K. E. Ridley: University of Cambridge
Z. Xu: University of Cambridge
I. Cimino: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
D. Rimmington: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
K. Rainbow: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
K. Duckett: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
S. Holmqvist: University of Cambridge
A. Khan: Wolfson Institute of Population Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
X. Dai: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London
E. G. Bochukova: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London
R. C. Trembath: King’s College London
H. C. Martin: Wellcome Sanger Institute, Hinxton
A. P. Coll: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
D. H. Rowitch: University of Cambridge
N. J. Wareham: MRC Epidemiology Unit, Wellcome–MRC Institute of Metabolic Science, University of Cambridge
D. A. van Heel: Wolfson Institute of Population Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
N. Timpson: University of Bristol
R. B. Simerly: Vanderbilt University
K. K. Ong: MRC Epidemiology Unit, Wellcome–MRC Institute of Metabolic Science, University of Cambridge
R. D. Cone: University of Michigan
C. Langenberg: MRC Epidemiology Unit, Wellcome–MRC Institute of Metabolic Science, University of Cambridge
J. R. B. Perry: MRC Epidemiology Unit, Wellcome–MRC Institute of Metabolic Science, University of Cambridge
G. S. Yeo: Wellcome–MRC Institute of Metabolic Science, University of Cambridge
S. O’Rahilly: Wellcome–MRC Institute of Metabolic Science, University of Cambridge

Nature, 2021, vol. 599, issue 7885, 436-441

Abstract: Abstract The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Date: 2021
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DOI: 10.1038/s41586-021-04088-9

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