Protein in the brain uses energy status to influence maturation, body
size

Date:
November 3, 2021
Source:
University of Michigan
Summary:
Scientists have identified how a protein in the brain uses
information about the body's energy balance to regulate growth
rate and the onset of puberty in children.



FULL STORY ========================================================================== Scientists have identified how a protein in the brain uses information
about the body's energy balance to regulate growth rate and the onset
of puberty in children.


==========================================================================
The research, scheduled to publish Nov. 3 in the journal Nature,
centered on the melanocortin 3 receptor (MC3R), a member of a family of proteins that have long been known to play central roles in metabolism
and energy balance.

University of Michian physiologist Roger Cone and colleagues discovered
the MC3R gene more than 20 years ago and demonstrated that mice lacking
this protein exhibit reduced linear growth, reduced lean mass and
increased obesity.

Subsequent studies published by Cone's group also demonstrated a role for
the receptor in regulating the interaction between reproduction and energy state, including the increased feeding and weight gain during pregnancy.

Now, an international team of scientists led by Sir Stephen O'Rahilly at
the Wellcome-MRC Institute of Metabolic Science, University of Cambridge,
has revealed for the first time how defects in the MC3R translate to
humans -- with results strikingly similar to the findings in mice.

The O'Rahilly team reports identification of the first individual with mutations in both copies of the MC3R gene, leaving the person with no functioning MC3R. Such cases are extremely rare, perhaps occurring in
as little as one in a billion people. This individual showed phenotypes,
or physical traits, that were nearly identical to mice with no MC3R.

Using data from UK Biobank and the Avon Longitudinal Study of Parents and Children, the team analyzed the phenotypes in volunteers with mutations in
one copy of the gene that encodes the MC3R. These individuals displayed
shorter body height and reduced lean mass compared with those who had
no MC3R mutations.

"In terms of melanocortins, every phenotype that we have observed in the
mouse has ultimately been found to be replicated in humans," said Cone, director of the U-M Life Sciences Institute and an author of the new
study. "This direct correlation between animal models and humans is not
always the case; but this research shows that mice are a near-perfect
model for studying human syndromes related to melanocortin receptors." Additionally, O'Rahilly discovered one new phenotype in people with MC3R mutations: a long delay in the onset of puberty in the patient lacking
MC3R, and subtle but significant delays in volunteers from the UK Biobank
with mutations in only one copy of the gene. Due to the discovery of
only a single patient with loss of both copies of the MC3R gene, the researchers also used mouse gene knockout models to confirm and further understand the findings.

New data generated by the Cone lab and collaborator Richard Simerly at
the Vanderbilt School of Medicine, and published in this latest study,
verify this effect and also argue that MC3R plays a role in communicating nutritional deprivation to the reproductive axis.

When mice are fasted for 24 hours, the MC3R detects the lack of energy
stores in the body and relays that information to the part of the brain
that regulates reproductive cycles. In normal mice, the reproductive
cycles halt until energy stores return to normal, post-fasting. In
mice with no MC3R, however, there is no change to the reproductive axis following fasting, indicating that communication about the energy balance
has stopped.

"These types of experiments give us important new understanding of
the body's metabolic and reproductive pathways, but they obviously
cannot be done in humans," said Cone, who is also a professor of
molecular and integrative physiology at the U-M Medical School. "This
research illustrates the critical role of animal models for studying the fundamentals of physiology, which can then be translated to human health
and disease." The research was supported by the National Institutes of
Health (United States), the UK Medical Research Council, Wellcome and
the National institute for Health Research (United Kingdom).

========================================================================== Story Source: Materials provided by University_of_Michigan. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. B. Y. H. Lam, A. Williamson, S. Finer, F. R. Day, J. A. Tadross, A.

Gonc,alves 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, S. O'Rahilly. MC3R
links nutritional state to childhood growth and the timing of
puberty. Nature, 2021; DOI: 10.1038/s41586-021-04088-9 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211103140055.htm

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