Investigating Ghrelin's Role in Regulating Energy Homeostasis

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，每年大约有30万人的死亡与肥胖和超重有关。 生长激素释放肽是一种主要在胃中发现的肽，对脑垂体释放生长激素具有强有力的刺激作用，最近发现的生长激素释放肽使人们对能量平衡的调节有了新的认识。 Ghrelin具有促脂肪生成、促食欲和心血管作用，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激素释放肽对包括人类在内的脊椎动物生长和能量稳态的作用。 研究人员过去的工作已经从罗非鱼（一种广盐性鱼类）的胃中分离出生长激素释放肽，这种鱼具有与哺乳动物一样的强效生长激素释放活性，并提供了初步证据，表明生长激素释放肽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Ghrelin将刺激脂肪的产生，而不依赖于其GH刺激作用。 在本提案中，将使用CP-477335（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。 1）研究ghrelin和CP-477335是否改变罗非鱼的脂肪沉积，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)采用原代肝细胞培养物表征ghrelin和CP-477335对肝脏中脂肪沉积、PUFA代谢和生长因子产生的作用。 所提出的研究在其新奇方面的智力价值将为理解生长激素释放肽在指导脊椎动物代谢投资中的作用提供宝贵的基础。 迄今为止，还没有关于ghrelin在任何脊椎动物中调节PUFA代谢的作用的报道。 拟议的研究将提供一种比较方法，这将大大有助于了解和理解脊椎动物如何分配可用的代谢能，这反过来又可用于开发适用于与病理生理条件相关的医学和药物/治疗的生物技术。

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.