Dataset Information

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

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.

SUBMITTER: Lam BYH

PROVIDER: S-EPMC8819628 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Lam B Y H BYH Williamson A A Finer S S Day F R FR Tadross J A JA Gonçalves Soares A A Wade K K Sweeney P P Bedenbaugh M N MN Porter D T DT Melvin A A Ellacott K L J KLJ Lippert R N RN Buller S S Rosmaninho-Salgado J J Dowsett G K C GKC Ridley K E KE Xu Z Z Cimino I I Rimmington D D Rainbow K K Duckett K K Holmqvist S S Khan A A Dai X X Bochukova E G EG Trembath R C RC Martin H C HC Coll A P AP Rowitch D H DH Wareham N J NJ van Heel D A DA Timpson N N Simerly R B RB Ong K K KK Cone R D RD Langenberg C C Perry J R B JRB Yeo G S GS O'Rahilly S S

Nature 20211103 7885

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development<sup>1</sup>. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure<sup>2</sup>. 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. ...[more]

PMID: 34732894

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Project description:The Karlberg model of human growth describes the infancy, childhood, and puberty (ICP) stages as continuous and overlapping, and defined by transitions driven by sequential additional effects of several endocrine factors that shape the growth trajectory and resultant adult size. Previous research has suggested that a delayed transition from the infancy to the childhood growth stage contributes to sub-optimal growth outcomes. A new method developed to analyze the structure of centile crossing in early life has emerged as a potential tool for identifying the infancy-childhood transition (ICT), through quantifying patterns of adjacent monthly weight-for-age z-score (WAZ) deviation correlations. Using this method, the infancy-childhood transition was identified as taking place at around 12 months of age in two cohorts of UK infants. Here, we apply this method to data collected as part of a longitudinal growth study in rural Gambia [the Hormonal and Epigenetic Regulators of Growth, or HERO-G study, N = 212 (F = 99, M = 113)], in order to identify the ICT and assess whether timing of this transition differs across groups based on sex or birth seasonality. We calculated Pearson correlation coefficients for adjacent monthly WAZ score deviations. Based on the patterns of change in the correlation structure over time, our results suggest that the infancy-childhood transition occurs at around 9 months of age in rural Gambian infants. This points to an accelerated ICT compared to UK infants, rather than a delayed ICT. A comparatively later transition, seen in UK infants, allows maximal extension of the high rates of growth during the infancy stage; an earlier transition as seen in Gambian infants cuts short this period of rapid growth, potentially impacting on growth outcomes in childhood while diverting energy into other processes critical to responses to acute infectious challenges. Growth in later developmental stages in this population offers an extended window for catch-up.

Dataset Information

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

Publications

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

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