Mechanisms of Central Leptin Resistance in Obesity

描述(申请人提供)：肥胖症与美国的主要健康成本有关，影响着超过1.2亿人，包括越来越多的儿童。超重和肥胖的根本原因尚不清楚。瘦素是一种脂肪衍生的激素，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而发生的，从而抑制食欲和刺激能量消耗。然而，由于未知的原因，瘦素在减轻肥胖动物和人类的体重和脂肪质量方面无效。这项建议旨在增加对这一问题的了解。 给予西式高脂肪饮食的正常小鼠会出现进行性肥胖和瘦素抵抗。因此，这项资助的一个中心目标是使用这个被广泛接受的人类肥胖的小鼠模型来确定这些动物为什么会肥胖，为什么它们对瘦素有抵抗力。我们开发了一种高度敏感的免疫组织化学(IHC)方法来从解剖学上测量瘦素的作用，我们已经确定，在肥胖小鼠中，下丘脑的一个特定区域(弓状核)，而不是其他大脑区域，对瘦素具有选择性抵抗。在这项应用中，我们将确定下丘脑瘦素抵抗的机制(S)。我们的总体假设是，弓状核中有缺陷的瘦素作用在DIO小鼠肥胖的发展中发挥了作用。这些研究的结果将极大地增加我们对瘦素抵抗肥胖症发展的理解，并可能有助于揭示体重调节和对高脂肪西方饮食的敏感性所涉及的关键机制。最终，这项提案的发现可能有助于确定新的抗肥胖药物--靶点，最终可能导致开发针对肥胖人类的新疗法。

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.