Regulation of energy rheostasis by the melanocortin-3 receptor

Science Advances
Masoud Ghamari-LangroudiRoger D Cone

Abstract

Like most homeostatic systems, adiposity in mammals is defended between upper and lower boundary conditions. While leptin and melanocortin-4 receptor (MC4R) signaling are required for defending energy set point, mechanisms controlling upper and lower homeostatic boundaries are less well understood. In contrast to the MC4R, deletion of the MC3R does not produce measurable hyperphagia or hypometabolism under normal conditions. However, we demonstrate that MC3R is required bidirectionally for controlling responses to external homeostatic challenges, such as caloric restriction or calorie-rich diet. MC3R is also required for regulated excursion from set point, or rheostasis, during pregnancy. Further, we demonstrate a molecular mechanism: MC3R provides regulatory inputs to melanocortin signaling, acting presynaptically on agouti-related protein neurons to regulate γ-aminobutyric acid release onto anorexigenic MC4R neurons, exerting boundary control on the activity of MC4R neurons. Thus, the MC3R is a critical regulator of boundary controls on melanocortin signaling, providing rheostatic control on energy storage.

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Citations

Feb 28, 2019·The Journal of Endocrinology·Giulia Baldini, Kevin D Phelan
Mar 31, 2019·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Clara Serra-JuhéJesús Argente
Mar 16, 2021·Frontiers in Physiology·Mingyang ChangRujun Gong
Mar 9, 2021·Molecular Metabolism·Giles S H YeoRoger A H Adan
Apr 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Patrick SweeneyRoger D Cone
Apr 23, 2021·Science Translational Medicine·Patrick SweeneyRoger D Cone
Aug 5, 2021·Biological Psychiatry·Francesca CopperiSabrina Diano
Aug 10, 2021·Neuropharmacology·Anna I DuniganAaron G Roseberry

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Methods Mentioned

BETA
Transgenic
restriction digests
enzyme-linked immunosorbent assay
NMR

Software Mentioned

Excel
Clampex
Promethion
GraphPad Prism

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