Mechanisms of Central Leptin Resistance in Obesity

描述（由申请人提供）：肥胖与美国的主要医疗费用有关，影响着超过1.2亿人，其中包括越来越多的儿童。造成超重和肥胖的根本原因尚不清楚。瘦素是一种脂肪来源的激素，通常可以减轻人类和啮齿动物的体重。这是通过对大脑的作用来抑制食欲和刺激能量消耗的。然而，由于未知的原因，瘦素对肥胖动物和人类的体重和脂肪质量无效。这项建议的目的是增加对这个问题的了解。

DESCRIPTION (provided by applicant): Obesity is associated with major health costs for the United States and affects more than 120 million people, including an increasing number of children. The underlying cause for the development of overweight and obesity is unknown. Leptin is a fat-derived hormone that normally reduces body weight in humans and in rodents. This occurs via actions on the brain leading to inhibition of appetite and stimulation of energy expenditure. However, for unknown reasons leptin is ineffective to reduce body weight and fat mass in obese animals and humans. This proposal is aimed at increasing the understanding of this issue. Normal mice given a Western-style high fat diet develop progressive obesity and leptin resistance. A central goal of this grant is therefore to use this widely accepted mouse-model of human obesity to determine why these animals become obese and why they are resistant to leptin. We have developed a highly sensitive immunohistochemical (IHC) method to anatomically measure leptin action and we have already determined that a specific region (arcuate nucleus) of the hypothalamus, but not other brain regions, is selectively resistant to leptin in obese mice. We will in this application determine the mechanism(s) of leptin resistance in the hypothalamus. Our overall hypothesis is that defective leptin action in the arcuate nucleus plays a role in development of obesity in DIO mice. Results from these studies would greatly increase our understanding of development of leptin-resistant obesity, and may help to unravel key mechanisms involved in body-weight regulation and sensitivity to a high-fat-containing Western diet. Ultimately, findings from this proposal may help to identify novel anti-obesity drug-targets that can eventually lead to development of new treatments for obese humans.