Investigating Ghrelin's Role in Regulating Energy Homeostasis

肥胖是许多疾病的主要风险因素，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。Ghrelin是一种主要在胃中发现的多肽，对脑下垂体释放生长激素具有强大的刺激作用。最近发现的Ghrelin为能量平衡的调节带来了新的理解。Ghrelin被认为具有成脂、增氧和心血管作用，这些作用可能独立于其GH刺激作用。拟议研究的总体目标是阐明Ghrelin对包括人类在内的脊椎动物的生长和能量动态平衡的作用。PIs过去的工作已经从罗非鱼的胃中分离出Ghrelin，这是一种泛盐生鱼类，与哺乳动物一样具有强大的GH释放活性，并提供了初步证据，表明Ghrelin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，而不依赖于它的GH刺激作用。在这项建议中，将以CP-477335(一种具有口服活性的生长激素刺激物)和鱼类(罗非鱼)为模型，阐明Ghrelin对能量稳态的作用模式。这项建议的具体目的是：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，以及生长因子及其结合蛋白的产生。2)通过原代肝细胞培养，研究Ghrelin和CP-477335对大鼠肝脏脂肪沉积、多不饱和脂肪酸代谢和生长因子产生的影响。拟议的研究具有新颖性，其学术价值将为理解Ghrelin在指导脊椎动物代谢投资方面的作用提供宝贵的基础。到目前为止，还没有关于Ghrelin对脊椎动物PUFA代谢的调节作用的报道。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代谢能量，这些能量反过来可用于开发适用于与病理生理条件相关的药物和药物/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.