Functional modulation of ovine and human somatotropes by in vitro application of leptin

肥胖在发达国家是一种常见的疾病，也是一种经常被污名化的普遍状况。精算数据表明，当身体质量指数（体重以公斤为单位的平方乘以身高以米为单位）超过理想值20%或更多时，预期寿命就会缩短（肥胖比理想值高出28%）。来自脑垂体的生长激素（GH）是增加肌肉和减少脂肪的主要合成代谢激素。在肥胖人群中，生长激素显著减少。事实上，内脏脂肪量是中年男性和女性生长激素分泌的主要负统计决定因素。很明显，生长激素的减少是由于生长激素细胞对来自大脑的GH释放激素（GHRH）的敏感性较低。因此，有必要了解肥胖患者垂体GH细胞的变化。最近发现的一种脂肪细胞分泌的多肽（瘦素）被证明可以减少食物摄入，增加能量消耗。瘦素受体存在于垂体中，主要存在于生长激素分泌细胞中。在我们的初步实验中，瘦素通过减少GHRH受体的合成来减少GH的分泌。同时，这种瘦素处理增加了GH释放肽（GHRP）的受体，GHRP是一种刺激GH分泌的合成肽。我们旨在通过研究激素和受体合成、细胞内信号分子、膜离子通道和细胞分泌机制等重要细胞功能，探讨瘦素对培养的羊和人生长激素细胞的影响。结果将阐明肥胖患者生长激素缺乏的机制。我们还将在体外测试合成GHRP与瘦素联合使用的效果。GHRP和瘦素在GH细胞功能修饰中的关系也将被进一步研究。很可能看到GHRP降低了瘦素对GH细胞的抑制作用。这可能最终导致GHRP（口服）在肥胖治疗中的有效应用。

Obesity is a common disorder in developed countries and a prevalent condition which is often stigmatized. Actuarial data indicate that life expectancy is reduced when body-mass index (body mass in kg-square of the height in metres) is 20% or more above the ideal (obesity is >28% above ideal). Growth hormone (GH) from pituitary gland is the major anabolic hormone to increase muscle and reduce fat. A significant reduction in GH is found in obesity. Indeed, visceral fat mass is primary negative statistical determinant of GH secretion in middle age men and women. It is clear that the reduction in GH is due to a low sensitivity of GH cells to GH-releasing hormone (GHRH) from brain. It is therefore necessary to understand the change of pituitary GH cells in obesity. A recently identified, fat cell secreted, polypeptide (leptin) is demonstrated to reduce food intake and increase energy expenditure. Receptors for leptin have been found in pituitary gland, mainly in GH secreting cells. In our preliminary experiments, leptin reduces GH secretion by decreasing GHRH receptor synthesis. Meanwhile, this leptin treatment increased the receptors for GH-releasing peptide (GHRP), a synthetic peptide stimulating GH secretion. We aim to investigate the effect of leptin on cultured ovine and human GH cells by studying important cell functions including hormone and receptors synthesis, intracellular signaling molecules, membrane ion channels and cellular secreting machinery. The results will clarify the mechanism underlying GH deficiency in obese patients. We will also test the effect of synthetic GHRP in combination with leptin in vitro. The relationship between GHRP and leptin on the functional modification of GH cells will also be studied. It is likely to see that GHRP reduces the inhibitory effect of leptin on GH cells. This may end up an effective therapeutical use of GHRP (oral available) in the treatment of obesity.