Université de Paris, UMRS_1266 INSERM, Institute of Psychiatry and Neuroscience of Paris, Paris, France.
Endocrine Research Unit, Department of Medicine, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, New York, USA.
Neuroendocrinology. 2022;112(3):215-234. doi: 10.1159/000516147. Epub 2021 Mar 26.
While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in 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.
We assessed the sex-specific contribution of GHS-R1a signaling in 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.
Adult Ghsr-/- male and female mice displayed deficits in weight and linear growth that were 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 occurring 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.
尽管绝大多数研究都集中在 ghrelin 或其受体 GHS-R1a 在生长、摄食和代谢中的作用，但对该系统中的性别差异知之甚少。此外，GHS-R1a 信号在控制脉冲式 GH 分泌及其与生长或代谢参数的关系中的作用从未被描述过。
我们评估了 GHS-R1a 信号在青春期（5-6 周龄）或成年（10-19 周龄）GHS-R KO（Ghsr-/-）和 WT（Ghsr+/+）雄性和雌性小鼠的 GH/IGF-1 轴活性、代谢参数和摄食行为中的性别特异性贡献。
成年 Ghsr-/-雄性和雌性小鼠的体重和线性生长出现缺陷，仅雄性的 GH 垂体含量减少与之相关。GHS-R1a 缺失与雄性的摄食频率降低和摄食间隔增加以及下丘脑 GHRH 和 NPY mRNA 减少有关，而雌性则没有。在成年时，Ghsr-/-小鼠垂体离体培养物中的 GH 释放减少与性别无关。然而，在成年但不在青春期 Ghsr-/-雌性小鼠中，体内脉冲式 GH 分泌减少，而在雄性中，GHS-R1a 缺失与青春期特有的脉冲式 GH 分泌减少有关。在雄性中，线性生长与脉冲式 GH 分泌无关，但与 ApEn 相关，ApEn 反映了节律性分泌的不规则性。脂肪量、血浆瘦素浓度或活动度不能预测 GH 分泌的差异。
讨论/结论：这些结果表明，GHS-R1a 信号对调节脉冲式 GH 分泌和摄食模式具有性别依赖性的二态作用，并且在成年雄性和雌性 GHS-R1a 缺失后，下丘脑出现不同的补偿机制。总的来说，我们表明 GHS-R1a 信号在雄性青春期和雌性成年期对脉冲式 GH 分泌的调节中发挥更关键的作用。
