Hyperphagia in male melanocortin 4 receptor deficient mice promotes growth independently of growth hormone

Tan, H. Y., Steyn, F. J., Huang, L., Cowley, M., Veldhuis, J. D. and Chen, C. (2016) Hyperphagia in male melanocortin 4 receptor deficient mice promotes growth independently of growth hormone. Journal of Physiology, 594 24: 7309-7326. doi:10.1113/JP272770


Author Tan, H. Y.
Steyn, F. J.
Huang, L.
Cowley, M.
Veldhuis, J. D.
Chen, C.
Title Hyperphagia in male melanocortin 4 receptor deficient mice promotes growth independently of growth hormone
Journal name Journal of Physiology   Check publisher's open access policy
ISSN 1469-7793
0022-3751
Publication date 2016-12-15
Sub-type Article (original research)
DOI 10.1113/JP272770
Open Access Status Not yet assessed
Volume 594
Issue 24
Start page 7309
End page 7326
Total pages 18
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Collection year 2017
Language eng
Abstract Key points: Loss of function of the melanocortin 4 receptor (MC4R) results in hyperphagia, obesity and increased growth. Despite knowing that MC4Rs control food intake, we are yet to understand why defects in the function of the MC4R receptor contribute to rapid linear growth. We show that hyperphagia following germline loss of MC4R in male mice promotes growth while suppressing the growth hormone–insulin-like growth factor-1 (GH–IGF-1) axis. We propose that hyperinsulinaemia promotes growth while suppressing the GH–IGF-1 axis. It is argued that physiological responses essential to maintain energy flux override conventional mechanisms of pubertal growth to promote the storage of excess energy while ensuring growth. Abstract: Defects in melanocortin-4-receptor (MC4R) signalling result in hyperphagia, obesity and increased growth. Clinical observations suggest that loss of MC4R function may enhance growth hormone (GH)-mediated growth, although this remains untested. Using male mice with germline loss of the MC4R, we assessed pulsatile GH release and insulin-like growth factor-1 (IGF-1) production and/or release relative to pubertal growth. We demonstrate early-onset suppression of GH release in rapidly growing MC4R deficient (MC4RKO) mice, confirming that increased linear growth in MC4RKO mice does not occur in response to enhanced activation of the GH–IGF-1 axis. The progressive suppression of GH release in MC4RKO mice occurred alongside increased adiposity and the progressive worsening of hyperphagia-associated hyperinsulinaemia. We next prevented hyperphagia in MC4RKO mice through restricting calorie intake in these mice to match that of wild-type (WT) littermates. Pair feeding of MC4RKO mice did not prevent increased adiposity, but attenuated hyperinsulinaemia, recovered GH release, and normalized linear growth rate to that seen in pair-fed WT littermate controls. We conclude that the suppression of GH release in MC4RKO mice occurs independently of increased adipose mass, and is a consequence of hyperphagia-associated hyperinsulinaemia. It is proposed that physiological responses essential to maintain energy flux (hyperinsulinaemia and the suppression of GH release) override conventional mechanisms of pubertal growth to promote the storage of excess energy while ensuring growth. Implications of these findings are likely to extend beyond individuals with defects in MC4R signalling, encompassing physiological changes central to mechanisms of growth and energy homeostasis universal to hyperphagia-associated childhood-onset obesity.
Keyword Energy homeostasis
Growth
Hyperinsulinemia
Hyperphagia
Melanocortin 4 receptor
Obesity
Puberty
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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School of Biomedical Sciences Publications
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