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.
Original language | English (US) |
---|---|
Pages (from-to) | 436-441 |
Number of pages | 6 |
Journal | Nature |
Volume | 599 |
Issue number | 7885 |
Early online date | Nov 3 2021 |
DOIs | |
State | Published - Nov 18 2021 |
Externally published | Yes |
ASJC Scopus subject areas
- General
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In: Nature, Vol. 599, No. 7885, 18.11.2021, p. 436-441.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - MC3R links nutritional state to childhood growth and the timing of puberty
AU - Genes & Health Research Team
AU - Lam, B. Y.H.
AU - Williamson, A.
AU - Finer, S.
AU - Day, F. R.
AU - Tadross, J. A.
AU - Gonçalves Soares, A.
AU - Wade, K.
AU - Sweeney, P.
AU - Bedenbaugh, M. N.
AU - Porter, D. T.
AU - Melvin, A.
AU - Ellacott, K. L.J.
AU - Lippert, R. N.
AU - Buller, S.
AU - Rosmaninho-Salgado, J.
AU - Dowsett, G. K.C.
AU - Ridley, K. E.
AU - Xu, Z.
AU - Cimino, I.
AU - Rimmington, D.
AU - Rainbow, K.
AU - Duckett, K.
AU - Holmqvist, S.
AU - Khan, A.
AU - Dai, X.
AU - Bochukova, E. G.
AU - Trembath, R. C.
AU - Martin, H. C.
AU - Coll, A. P.
AU - Rowitch, D. H.
AU - Wareham, N. J.
AU - van Heel, D. A.
AU - Timpson, N.
AU - Simerly, R. B.
AU - Ong, K. K.
AU - Cone, R. D.
AU - Langenberg, C.
AU - Perry, J. R.B.
AU - Yeo, G. S.
AU - O’Rahilly, S.
N1 - analysis were supported by the UK Medical Research Council (MRC) Metabolic Diseases Unit (MC_UU_00014/1), Wellcome (WT 095515/Z/11/Z) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. K.R., K.D., D.R., I.C., A.P.C. and G.S.Y. are supported by the MRC Metabolic Disease Unit (MC_UU_00014/1). S.O. is supported by a Wellcome Investigator award (WT 095515/Z/11/Z) and the NIHR Cambridge Biomedical Research Centre. B.Y.H.L. is supported by a Biotechnology and Biological Sciences Research Council (BBSRC) Project Grant (BB/S017593/1). A.W. and S.B. hold PhD studentships supported by Wellcome. J.A.T. is supported by an NIHR Clinical Lectureship (CL-2019-14-504). A.M. holds a PhD studentship supported jointly by the University of Cambridge Experimental Medicine Training Initiative programme in partnership with AstraZeneca (EMI-AZ). G.K.C.D. is supported by the BBSRC Doctoral Training Programme. Next-generation sequencing was performed via Wellcome\u2013MRC IMS Genomics and transcriptomics core facility supported by the MRC (MC_UU_00014/5) and the Wellcome (208363/Z/17/Z) and the Cancer Research UK Cambridge Institute Genomics Core. The histology core is supported by the MRC (MC_UU_00014/5). We thank P. Barker and K. Burling of the Cambridge NIHR Biomedical Research Centre Clinical Biochemistry Assay Laboratory for their assistance with biochemical assays. The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the MRC (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the MRC (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372. We are grateful to all of the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The Fenland study (https://doi.org/10.22025/ 2017.10.101.00001) is funded by the MRC (MC_UU_12015/1). We are grateful to all of the volunteers and to the general practitioners and practice staff for assistance with recruitment. We thank the Fenland study investigators, Fenland study co-ordination team and the Epidemiology Field, Data and Laboratory teams. We further acknowledge support for genomics and metabolomics from the MRC (MC_PC_13046). Proteomic measurements were supported and governed by a collaboration agreement between the University of Cambridge and Somalogic. F.R.D., N.J.W., K.K.O., C.L. and J.R.B.P. are funded by the MRC (MC_UU_12015/1, MC_UU_12015/2, MC_UU_00006/1 and MC_UU_00006/2). N.J.W. is an NIHR Senior Investigator. We are grateful for funding to the BIA prediction equations, supported by the NIHR Biomedical Research Centre Cambridge (IS-BRC-1215-20014). The NIHR Cambridge Biomedical Research Centre is a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. We thank A. Mesut Erzurumluoglu, L. Wittemans, E. Wheeler, I. Stewart, M. Pietzner, M. Koprulu, E. De Lucia Rolfe, R. Powell and N. Kerrison for providing help with and access to GWAS meta-analysis summary statistics for body composition measures and biomarkers in the UKBB, metabolomics measures in the EPIC-Norfolk study, proteomics measures in the MRC Fenland study, as well as help with genotype quality control in the Fenland study and the UKBB. The MRC, Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genome-wide association data were generated by sample logistics and genotyping facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A.G.S. was supported by the study of \u2018Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases\u2019 (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). K.W. was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Institutional Strategic Support Fund (204813/Z/16/Z). N.T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the principal investigator of the ALSPAC (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MC_UU_00011) and works within the Cancer Research UK Integrative Cancer Epidemiology Programme (C18281/A19169). We are extremely grateful to all of the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The Rowitch laboratory receives funding from Wellcome and the ERC Advanced Grant (REP-789054-1). Genes & Health is/has recently been core funded by Wellcome (WT102627 and WT210561), the MRC (M009017), Higher Education Funding Council for England Catalyst, Barts Charity (845/1796), Health Data Research UK (for London substantive site), and research delivery support from the NHS NIHR Clinical Research Network (North Thames). Additional funding for recall was provided by a pump priming award to S.F. (SCA/PP/12/19) from the Diabetes Research and Wellness Foundation. E.G.B. and X.D. are supported by the Wellcome (208987/Z/17/Z) and Barts Charity (project grant to E.G.B.). We thank Social Action for Health, Centre of The Cell, members of our Community Advisory Group, and staff who have recruited and collected data from volunteers; the NIHR National Biosample Centre (UK Biocentre), the Social Genetic and Developmental Psychiatry Centre (King\u2019s College London), Wellcome Sanger Institute, and Broad Institute for sample processing, genotyping, sequencing and variant annotation; Barts Health NHS Trust, NHS Clinical Commissioning Groups (Hackney, Waltham Forest, Tower Hamlets and Newham), East London NHS Foundation Trust, Bradford Teaching Hospitals NHS Foundation Trust, and Public Health England (especially D. Wyllie) for GDPR-compliant data sharing; and most of all, we thank all of the volunteers participating in Genes & Health. R.D.C. receives funding from US National Institutes of Health (NIH) grants DK070332 and DK126715. P.S. is funded by NIH F32HD095620 and K99DK127065. R.B.S. receives funding from the NIH (DK106476). M.N.B. is funded by the NIH (F32DK123879). This research has been conducted using data from UK Biobank, a major biomedical database (https://www.ukbiobank.ac.uk), application numbers 32974 and 44448. Competing interests S.O. has undertaken remunerated consultancy work for Pfizer, AstraZeneca, GSK and ERX Pharmaceuticals. D.A.v.H. has an unrestricted research grant from Alnylam Pharmaceuticals. P.S. and R.D.C. hold equity in Courage Therapeutics Inc. and are inventors of intellectual property optioned to Courage Therapeutics Inc. R.D.C. chairs the Scientific Advisory Board at Courage Therapeutics Inc. All remaining authors declare no competing interests.
PY - 2021/11/18
Y1 - 2021/11/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85118836415&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118836415&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04088-9
DO - 10.1038/s41586-021-04088-9
M3 - Article
C2 - 34732894
AN - SCOPUS:85118836415
SN - 0028-0836
VL - 599
SP - 436
EP - 441
JO - Nature
JF - Nature
IS - 7885
ER -