Tan H Y, Steyn F J, Huang L, Cowley M, Veldhuis J D, Chen C
School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
The University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia.
J Physiol. 2016 Dec 15;594(24):7309-7326. doi: 10.1113/JP272770. Epub 2016 Oct 2.
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.
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.
黑皮质素4受体（MC4R）功能丧失会导致食欲亢进、肥胖和生长加速。尽管我们知道MC4R控制食物摄入，但我们仍不清楚MC4R受体功能缺陷为何会导致快速线性生长。我们发现，雄性小鼠中MC4R基因缺失后的食欲亢进会促进生长，同时抑制生长激素-胰岛素样生长因子-1（GH-IGF-1）轴。我们提出，高胰岛素血症在抑制GH-IGF-1轴的同时促进生长。有人认为，维持能量通量所必需的生理反应会超越青春期生长的传统机制，以促进多余能量的储存，同时确保生长。
黑皮质素-4-受体（MC4R）信号传导缺陷会导致食欲亢进、肥胖和生长加速。临床观察表明，MC4R功能丧失可能会增强生长激素（GH）介导的生长，尽管这一点尚未得到验证。我们使用MC4R基因缺失的雄性小鼠，评估了相对于青春期生长而言的脉冲式GH释放以及胰岛素样生长因子-1（IGF-1）的产生和/或释放情况。我们证明，在快速生长的MC4R缺陷（MC4RKO）小鼠中，GH释放会出现早期抑制，这证实了MC4RKO小鼠中线性生长的增加并非是由于GH-IGF-1轴的激活增强所致。MC4RKO小鼠中GH释放的逐渐抑制与肥胖增加以及与食欲亢进相关的高胰岛素血症的逐渐恶化同时发生。接下来，我们通过限制MC4RKO小鼠的热量摄入使其与野生型（WT）同窝小鼠相匹配，从而防止其食欲亢进。对MC4RKO小鼠进行配对喂养并不能防止肥胖增加，但能减轻高胰岛素血症，恢复GH释放，并使线性生长速率恢复到配对喂养的WT同窝对照小鼠的水平。我们得出结论，MC4RKO小鼠中GH释放的抑制独立于脂肪量的增加，是与食欲亢进相关的高胰岛素血症的结果。有人提出，维持能量通量所必需的生理反应（高胰岛素血症和GH释放的抑制）会超越青春期生长的传统机制，以促进多余能量的储存，同时确保生长。这些发现的影响可能不仅限于MC4R信号传导缺陷的个体，还包括与食欲亢进相关的儿童期肥胖普遍存在的生长和能量稳态机制中的核心生理变化。
