期刊
NATURE
卷 599, 期 7885, 页码 436-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-04088-9
关键词
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资金
- UK Medical Research Council (MRC) Metabolic Diseases Unit [MC_UU_00014/1]
- Wellcome [WT 095515/Z/11/Z, 208363/Z/17/Z, 217065/Z/19/Z, WT102627, WT210561, 208987/Z/17/Z]
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- MRC Metabolic Disease Unit [MC_UU_00014/1]
- Wellcome Investigator award [WT 095515/Z/11/Z]
- NIHR Cambridge Biomedical Research Centre
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/S017593/1]
- NIHR Clinical Lectureship [CL-2019-14-504]
- University of Cambridge Experimental Medicine Training Initiative programme
- AstraZeneca (EMI-AZ)
- BBSRC Doctoral Training Programme
- MRC [MC_UU_00014/5, MR/N003284/1, MC-UU_12015/1, MC_PC_13048, MC_UU_12015/1, MC_UU_12015/2, MC_UU_00006/1, MC_UU_00006/2, M009017]
- Cancer Research UK Cambridge Institute Genomics Core
- Cancer Research UK [C864/A14136]
- MRC Cambridge Initiative in Metabolic Science [MR/L00002/1]
- Innovative Medicines Initiative Joint Undertaking under EMIF grant [115372]
- NIHR Biomedical Research Centre Cambridge [IS-BRC-1215-20014]
- 23andMe
- H2020-SC1-2019-Single-Stage-RTD [874739]
- Elizabeth Blackwell Institute for Health Research
- University of Bristol
- Wellcome Institutional Strategic Support Fund [204813/Z/16/Z]
- University of Bristol NIHR Biomedical Research Centre [BRC-1215-2001]
- MRC Integrative Epidemiology Unit [MC_UU_00011]
- Cancer Research UK Integrative Cancer Epidemiology Programme [C18281/A19169]
- ERC Advanced Grant [REP-789054-1]
- Higher Education Funding Council for England Catalyst
- Barts Charity [845/1796]
- Health Data Research UK
- Diabetes Research and Wellness Foundation [SCA/PP/12/19]
- Barts Charity
- US National Institutes of Health (NIH) grants [DK070332, DK126715]
- NIH [F32HD095620, K99DK127065, DK106476, F32DK123879]
- MRC [MC_UU_00014/1] Funding Source: UKRI
- Wellcome Trust [204813/Z/16/Z, 095515/Z/11/Z, 208987/Z/17/Z] Funding Source: Wellcome Trust
MC3R regulates the timing of sexual maturation, linear growth rate, and accrual of lean mass, while MC4R controls appetite, food intake, and energy expenditure. Loss of MC3R leads to delayed puberty, reduced linear growth, and decreased lean mass, while loss of MC4R results in delayed sexual maturation and insensitivity of reproductive cycle length to nutritional perturbation.
The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development(1). The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure(2). 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 delayedsexual maturationand 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.
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