Investigating Ghrelin's Role in Regulating Energy Homeostasis

研究 Ghrelin 在调节能量稳态中的作用

• 批准号: 0417250
• 负责人: E. Gordon Grau
• 金额: --
• 依托单位: University of Hawaii
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0417250&HistoricalAwards=false
• 关键词: Investigating; Ghrelin; Role; Regulating; Energy

Obesity is a major risk factor for many diseases, including, but not limited to, diabetes, cancer, arthritis, high blood pressure and cardiovascular disease. In the United States, roughly 300,000 deaths per year are associated with obesity and overweight. The recent discovery of ghrelin, a peptide found primarily in the stomach with potent stimulatory action on growth hormone release from the pituitary gland, has brought a new understanding of the regulation of energy balance. Ghrelin has been suggested to possess adipogenic, orexigenic and cardiovascular actions that might be independent from its GH stimulatory actions. The overall goal of the proposed research is to clarify the actions of ghrelin on growth and energy homeostasis in vertebrates including humans. Past work by the PIs have isolated ghrelin from the stomach of the tilapia, a euryhaline fish, with a potent GH-releasing activity as in mammals, and has provided preliminary evidence that ghrelin stimulates appetite and body weight gain in the tilapia, which appears to be a result of increased fat deposition. The PIs hypothesize that ghrelin will stimulate the production of fat independent from its GH stimulatory actions. In this proposal the mode of actions of ghrelin on energy homeostasis will be clarified, using CP-477335 (an orally active GH stimulatory compound) and a fish (tilapia) as a model. The specific aims of this proposal are: 1) To investigate whether ghrelin and CP-477335 alter fat deposition, specifically polyunsaturated fatty acids (PUFA), and production of growth factors and their binding proteins in the tilapia. 2) To characterize the actions of ghrelin and CP-477335 on fat deposition, PUFA metabolism and on growth factor production in the liver using culture of primary hepatocytes. The intellectual merit of the proposed studies in its novelty will provide invaluable groundwork for the understanding of ghrelin's actions in directing metabolic investment in vertebrates. To date, there are no reports on the effect of ghrelin on regulating PUFA metabolism in any vertebrate. The proposed studies will provide a comparative approach that will contribute greatly to the knowledge and understanding of how vertebrates partition available metabolic energy, which in turn could be used for the development of biotechnologies applicable to medicine and drugs/treatment associated with pathophysiological conditions.

肥胖是许多疾病的主要危险因素，包括但不限于糖尿病、癌症、关节炎、高血压和心血管疾病。 在美国，每年约有 30 万人死亡与肥胖和超重有关。 最近发现的生长素释放肽（ghrelin）是一种主要存在于胃中的肽，对脑下垂体释放生长激素具有强效刺激作用，为能量平衡的调节带来了新的认识。 有人认为 Ghrelin 具有促进脂肪、促进食欲和心血管作用，这些作用可能与其 GH 刺激作用无关。 拟议研究的总体目标是阐明生长素释放肽对包括人类在内的脊椎动物的生长和能量稳态的作用。 PI过去的工作从罗非鱼（一种广盐性鱼类）的胃中分离出了生长素释放肽，与哺乳动物一样具有有效的生长激素释放活性，并提供了初步证据表明生长素释放肽可以刺激罗非鱼的食欲和体重增加，这似乎是脂肪沉积增加的结果。 PI 假设生长素释放肽会刺激脂肪的产生，而与它的 GH 刺激作用无关。 在该提案中，将使用 CP-477335（一种口服活性 GH 刺激化合物）和鱼（罗非鱼）作为模型，阐明 ghrelin 对能量稳态的作用模式。 该提案的具体目标是：1) 研究生长素释放肽和 CP-477335 是否改变罗非鱼中的脂肪沉积，特别是多不饱和脂肪酸 (PUFA) 以及生长因子及其结合蛋白的产生。 2) 使用原代肝细胞培养物来表征生长素释放肽和 CP-477335 对脂肪沉积、PUFA 代谢和肝脏中生长因子产生的作用。 拟议研究的新颖性及其智力价值将为理解生长素释放肽在指导脊椎动物代谢投资方面的作用提供宝贵的基础。 迄今为止，还没有关于ghrelin对任何脊椎动物调节PUFA代谢的影响的报道。 拟议的研究将提供一种比较方法，该方法将极大地有助于了解和理解脊椎动物如何分配可用的代谢能量，这反过来又可用于开发适用于与病理生理状况相关的医学和药物/治疗的生物技术。