The effect of ghrelin, leptin and orexins on the function of pituitary somatotropes in rat, mouse and human.

营养不良，如肥胖或消瘦综合征，伴有GH缺乏症。新发现的三种代谢调节激素，即来自脂肪组织的瘦素、来自胃的生长激素释放肽和来自下丘脑的食欲素，在调节食欲、能量消耗和肥胖中起重要作用。三种代谢调节激素的受体都存在于垂体GH分泌细胞（促生长细胞）中，积累的实验室数据表明三种激素对GH分泌的修饰。然而，报告了相互矛盾的结果。这三种激素的作用机制尚不清楚，代谢调节激素和内源性GH调节系统之间的相互关系也不清楚。我们建议通过研究瘦素、生长激素释放肽和食欲素对小鼠体内治疗和体外培养垂体细胞治疗的影响来澄清这个问题。测定垂体生长激素分泌、垂体生长激素及其调节激素受体的合成。我们还将使用生长激素细胞特异性标记绿色荧光信号的GH-GFP转基因小鼠，研究体内处理后小鼠垂体中生长激素细胞的形态学变化。通过完成这个项目，我们将能够（1）阐明代谢调节激素在控制GH水平中的生理作用，（2）阐明代谢调节激素在营养不良条件下发生的GH缺乏症中的病理作用。

Malnutrition such as obesity or wasting syndrome is accompanied by GH deficiency. Three newly discovered metabolic regulatory hormones, leptin from fat tissue, ghrelin from stomach and orexins from hypothalamus, play important roles in regulating appetite, energy expenditure, and adiposity. Receptors for three metabolic regulatory hormones are all present in pituitary GH secreting cells (somatotropes) and accumulated laboratory data indicate a modification of GH secretion by three hormones. Contradictory results have however been reported. Mechanisms of action of these three hormones are not clear and the interrelationship between metabolic regulatory hormones and intrinsic GH regulatory system is unknown. We propose to clarify this issue by investigating the effect of in vivo treatment of mice and in vitro treatment of cultured pituitary cells with leptin, ghrelin, and orexins. GH secretion, GH and GH-regulatory hormones' receptor synthesis in pituitary somatotropes will be measured. We will also use GH-GFP transgenic mice, in which somatotropes are specifically marked with green fluorescent signal, to study morphological change of somatotropes in mouse pituitary glands after in vivo treatment. By completing this project, we will be able (1) to clarify the physiological role of metabolic regulatory hormones in control of GH levels and (2) to clarify the pathological role of metabolic regulatory hormones in GH deficiency occurred in malnutritional conditions.