Gastrointestinal Hormonal Regulation of Obesity

描述（由申请人提供）： 项目摘要/摘要肥胖是我们VA医疗系统中发病率和死亡率的主要原因，占糖尿病、高血压、冠状动脉疾病和脑血管意外的大多数病例。对我们的肥胖老兵的体重调节的更好的理解将通过避免严重的医疗并发症和提出新的治疗方法来改善生活质量。 本研究的目的是证实高蛋白饮食对肥胖患者有效、安全和有益的减少食物摄入量和体重，并在相关实验模型中建立高蛋白饮食诱导早饱信号的神经激素机制，重点是激活胃迷走神经传入。 我们将评估高蛋白饮食对肥胖患者饱腹感和餐后肠道激素模式的影响。一项持续24-30个月的随机对照研究将志愿受试者（年龄30岁，BMI 27-40 kg/m2）分配到：1）极高蛋白饮食组，2）高蛋白饮食组，3）标准蛋白饮食组作为对照，热量相同。所有受试者将由营养师随访，并将进行循环肠道激素测定和生化测定。 通过药理学和电生理学方法测试高蛋白质释放的肠肽对肥胖大鼠迷走神经传入饱腹信号传导至大脑的增强作用的假设，评估高蛋白质饮食减少食物摄入的神经体液机制。此外，Fos免疫组织化学绘制高蛋白饮食引起的脑神经元激活将使我们能够建立高蛋白饮食与标准蛋白饮食激活的差异回路。 这些研究将为高蛋白饮食的减肥作用和餐后肠道激素释放谱的相关改变提供临床依据，并在肥胖实验模型中揭示神经元（迷走神经传入）水平的潜在机制。拟定的研究将解决有关饱腹感/体重调节机制的重要病理生理学问题，并提供潜在的重要临床治疗策略。 公共卫生相关性： 肥胖是VA医疗保健系统中一个不断升级的医疗问题。它是我们患者人群中出现慢性疾病的主要风险因素。这些疾病包括动脉硬化、糖尿病和某些形式的癌症，因此造成了很高的发病率和死亡率。2000年报告的一项最近的研究确定，在93，290名美国退伍军人中，68.4%至少超重，BMI >25 kg/m2，37.4%被归类为肥胖，BMI超过30 kg/m2。在1,710,032名男性中，73%被定义为超重，近33%被归类为肥胖。由于患病率在VA医疗保健系统中不断增加，减少肥胖的干预措施可能会为我们的患者人群带来积极的结果。鉴于VA医疗保健系统是美国同类系统中最大的，158家医疗机构包括超过500万名患者，降低肥胖相关发病率和死亡率的策略不仅可能对预防患者护理产生有益影响，而且还将节省大量资源，可以更好地用于退伍军人医疗保健的其他方面。

DESCRIPTION (provided by applicant): Project Summary/Abstract Obesity is a major cause of morbidity and mortality within our VA medical system accounting for the majority of cases of diabetes mellitus, hypertension, coronary artery disease and cerebrovascular accidents. An improved understanding of the regulation of body weight in our veteran obese patients will improve the quality of life by avoidance of serious medical complications and by suggesting novel therapeutic approaches. The objective of this study is to establish that a high protein diet is efficacious, safe and beneficial to curtail food intake and body weight in obese patients and to establish the neurohormonal mechanisms of high protein diet-induced early satiety signal in relevant experimental model, focusing on activation of gastric vagal afferents. We will assess the efficacy of a high protein diet on satiety and pattern of postprandial gut hormone in obese patients. A randomized controlled study lasting 24-30 months will assign volunteer subjects (ages e30, BMI 27-40 kg/m2) to: 1) Very high protein diet group, 2) High protein diet group, and 3) Standard protein diet group as control with same calories. All the subjects will be followed by a dietitian and determination of circulating gut hormone and biochemical assays will be performed. Neurohumoral mechanisms through which high protein diet curtailed food intake will be assessed by testing the hypthesis of a potentiating effect of gut peptides released by high protein on vagal afferent satieting signaling to the brain in obese rats using pharmacologica and electrophysiologic approaches. In addition Fos immunohistochemistry to map brain neuronal activation in respone to high protein diet will allow us to establish differential circuitries activated by high vs standard protein diet. These studies will provide a clinical basis on the weight reducing effect of high protein diet and the associated alterations in the profile of postprandial gut hormones released, and unravel the underlying mechanisms at the neuronal (vagal afferent) level in an expermental model of obesity. The proposed studies will address important pathophysiological questions regarding the mechanisms regulating satiety/body weight as well as provide potentially important clinical treatment strategies. PUBLIC HEALTH RELEVANCE: NARRATIVE Obesity is an escalating medical problem in the VA Healthcare System. It is a major risk factor for the development of chronic diseases seen in our patient population. These illnesses include arteriosclerosis, diabetes mellitus and certain forms of cancer and, therefore, accounts for significant morbidity and mortality. A recent study, reported in 2000, established that among 93,290 women American veterans, 68.4% were at least overweight with a BMI >25 kg/m2 and 37.4% were classified as obese with a BMI over 30 kg/m2. Of 1,710,032 men 73% were defined as overweight and nearly 33% were classified as obese. Since the prevalence is increasing in the VA Healthcare System, interventions to reduce obesity are likely to result in positive outcomes for our patient population. Given that the VA Medical Care System is the largest of its type in the USA, and that the 158 medical facilities include over 5 million patients, strategies to reduce the incidence of obesity-related morbidity and mortality are likely to have a beneficial impact not only on patient care through prevention but will result in a significant savings in resources that could be better spent on other aspects of veteran healthcare.