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

体外应用瘦素对绵羊和人类生长激素的功能调节

• 批准号: nhmrc : 169005
• 负责人: Prof Chen Chen
• 金额: $ 15.14万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2001
• 资助国家: 澳大利亚
• 起止时间: 2001-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/functional-modulation-ovine-application-leptin/77662
• 关键词: Functional; modulation; ovine; human; somatotropes

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.

肥胖症是发达国家的一种常见疾病，也是一种经常被污名化的流行病。精算数据表明，当身体质量指数（以公斤为单位的体重-身高的平方，以米为单位）比理想值高出20%或更多时（肥胖比理想值高出28%），预期寿命就会缩短。生长激素（GH）是脑垂体分泌的主要合成代谢激素，可增加肌肉和减少脂肪。在肥胖症中发现GH显著降低。事实上，内脏脂肪量是中年男性和女性GH分泌的主要负统计决定因素。很明显，GH的减少是由于GH细胞对来自脑的GH释放激素（GHRH）的低敏感性。因此，了解肥胖时垂体GH细胞的变化是十分必要的。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并增加能量消耗。瘦素受体存在于垂体，主要存在于GH分泌细胞。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分泌。同时，这种瘦素治疗增加了GH释放肽（GHRP）的受体，GHRP是一种刺激GH分泌的合成肽。我们的目的是研究瘦素对培养的绵羊和人GH细胞的重要功能，包括激素和受体的合成，细胞内信号分子，膜离子通道和细胞分泌机制的影响。这些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研究。很可能看到GHRP降低瘦素对GH细胞的抑制作用。这可能最终成为一个有效的治疗使用GHRP（口服）在治疗肥胖症。