Introduction. While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, on growth, feeding and metabolism has been conducted in male rodents, very little is known about sex differences in this system. Furthermore, the role of GHS-R1a signaling in the control of pulsatile GH secretion and its link with growth or metabolic parameters has never been characterized. Methods. We assessed the sex-specific contribution of GHS-R1a signaling on the activity of the GH/IGF-1 axis, metabolic parameters and feeding behavior in adolescent (5-6 weeks old) or adult (10-19 weeks old) GHS-R KO (Ghsr-/-) and WT (Ghsr+/+) male and female mice. Results. Adult Ghsr-/- male and female mice displayed deficits in weight and linear growth that was correlated with reduced GH pituitary contents in males only. GHS-R1a deletion was associated with reduced meal frequency and increased meal intervals, as well as reduced hypothalamic GHRH and NPY mRNA in males, not females. In adult, GH release from Ghsr-/- mice pituitary explants ex vivo was reduced independently of the sex. However, in vivo pulsatile GH secretion decreased in adult but not adolescent Ghsr-/- females, while in males, GHS-R1a deletion was associated with reduction in pulsatile GH secretion during adolescence exclusively. In males, linear growth did not correlate with pulsatile GH secretion, but rather with ApEn, a measure that reflects irregularity of the rhythmic secretion. Fat mass, plasma leptin concentrations or ambulatory activity did not predict differences in GH secretion. Discussion/Conclusion. These results point to a sex-dependent dimorphic effect of GHS-R1a signaling to modulate pulsatile GH secretion and meal pattern in mice with different compensatory mechanisms occuring in the hypothalamus of adult males and females after GHS-R1a deletion. Altogether, we show that GHS-R1a signaling plays a more critical role in the regulation of pulsatile GH secretion during adolescence in males and adulthood in females.


中文翻译：

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GHS-R缺失对雄性和雌性小鼠生长、搏动性GH分泌和膳食模式的影响

介绍。虽然绝大多数研究生长素释放肽或其受体 GHS-R1a 对生长、摄食和新陈代谢的作用都是在雄性啮齿动物身上进行的，但对该系统的性别差异知之甚少。此外，GHS-R1a 信号在控制脉动 GH 分泌中的作用及其与生长或代谢参数的联系从未被描述过。方法。我们评估了 GHS-R1a 信号传导对青少年（5-6 周龄）或成人（10-19 周龄）GHS-R 的 GH/IGF-1 轴活动、代谢参数和摄食行为的性别特异性贡献KO (Ghsr-/-) 和 WT (Ghsr+/+) 雄性和雌性小鼠。结果。成年 Ghsr-/- 雄性和雌性小鼠在体重和线性生长方面表现出缺陷，这与仅雄性的 GH 垂体含量减少有关。GHS-R1a 缺失与减少进餐频率和增加进餐间隔有关，以及减少男性下丘脑 GHRH 和 NPY mRNA，而不是女性。在成人中，来自 Ghsr-/- 小鼠垂体外植体的 GH 释放减少，与性别无关。然而，在成年期而非青春期 Ghsr-/- 女性体内，脉动 GH 分泌减少，而在男性中，GHS-R1a 缺失仅与青春期脉动 GH 分泌减少有关。在男性中，线性生长与搏动的 GH 分泌无关，而是与 ApEn 相关，ApEn 是一种反映节律性分泌不规则的测量值。脂肪量、血浆瘦素浓度或动态活动不能预测 GH 分泌的差异。讨论/结论。这些结果表明 GHS-R1a 信号传导的性别依赖性二态效应可调节 GHS-R1a 缺失后成年雄性和雌性下丘脑中发生不同代偿机制的小鼠的脉动 GH 分泌和膳食模式。总之，我们表明 GHS-R1a 信号传导在调节男性青春期和女性成年期的脉动 GH 分泌中发挥着更关键的作用。