Administrative Core

描述(由申请人提供)： 尽管科学和医疗保健专业为了解和成功治疗肥胖症做出了相当大的努力，但肥胖症的发病率仍在继续上升，与肥胖症相关的社会成本也令人震惊。这一问题的严重性反映在世界卫生组织和国家卫生研究院最近的调查和目标中。近年来，两个因素被曝光，这两个因素揭示了这个问题的基本方面，并可能成为未来治疗的关键。第一个因素是，人体拥有一个非常有效的调节系统，可以维持体内特定数量的脂肪。这种脂肪量在不同的环境中可能会有所不同，而且肯定会在不同的人之间有很大的不同。尽管如此，在恒定的环境中，个体会以脂肪的形式严格保护特定数量的总储存能量。关于人类肥胖的第二个主要因素是，当经常摄入饱和脂肪含量高的饮食时，身体防御的储存脂肪的数量会增加。因此，流行病学研究发现，各国平均膳食脂肪摄入量与肥胖及其相关并发症和危险因素的发生率之间存在显著的相关性。当饮食中的平均脂肪量随着时间的推移而增加时，就像过去30年里在许多国家发生的那样，肥胖症的发生率也会增加。关键的一点是，当个人长期暴露在较高的平均膳食饱和脂肪水平下时，原本令人难以置信的强大的负反馈系统调节身体脂肪滑落。更多的脂肪被储存起来，个体走向肥胖。正是这两个因素的相互作用，才是本提案的主题。更具体地说，在三个相互关联的项目中，我们询问高饱和脂肪饮食的摄入如何改变决定身体脂肪和患糖尿病易感性的一些关键因素。项目1的重点是肠道和中枢神经系统载脂蛋白A-IV如何调节食物摄入量，以及如何通过不同脂肪含量和类型的饮食来改变。项目2测试了几个假设，即饱和脂肪和单一不饱和脂肪如何影响胰岛β细胞对增加胰岛素抵抗的适应。项目3试图阐明中枢神经系统中有助于防御高饱和脂肪饮食中增加的体脂的机制。

DESCRIPTION (provided by applicant): In spite of considerable effort by the scientific and healthcare professions to understand and successfully treat obesity, its incidence continues to rise and the obesity-related costs to society are staggering. The enormity of the problem is reflected in recent surveys and goals of the World Health Organization and the National Institutes of Health. Two factors have come to light in recent years that shed light on fundamental aspects of the problem and may hold a key for future therapies. The first factor is that the body possesses a remarkably efficient regulatory system that works to maintain a particular amount of fat in the body. This amount of fat may vary in different environments, and it certainly varies considerably among individuals. Nonetheless, in a constant environment, individuals rigorously defend a particular amount of total stored energy in the form of fat. The second major factor concerning human obesity is that when a diet with a high saturated fat content is consumed on a regular basis, the amount of stored fat that the body defends increases. Hence, epidemiological studies have identified a significant correlation between average dietary fat intake and the incidence of obesity and its related complications mad risk factors among nations. And when the average amount of fat in the diet increases over time, as has occurred in many nations over the past thirty years, the incidence of obesity also increases. The key point is that when individuals are exposed, on a chronic basis, to a higher average level of dietary saturated fat, the otherwise incredibly robust negative feedback system that regulates body fat slips. More fat is stored and the individual moves toward obesity. It is the interaction of these two factors that is the subject of this proposal. More specifically, over three interrelated projects, we ask how consumption of a high saturated fat diet modifies a number of critical factors that determine body fat and the predisposition to become diabetic. Project 1 focuses on how the gut and CNS protein Apo A-IV regulate food intake and can be altered by diets with different amounts and types of fat. Project 2 tests several hypotheses about how saturated versus monounsaturated fats influence the adaptation of the pancreatic beta-cell to increasing insulin resistance. Project 3 seeks to elucidate the mechanisms in the CNS that contribute to the defense of increased body fat that occurs on high saturated fat diet.