Leptin in Vascular Disease

描述（由申请人提供）：瘦素是一种由脂肪细胞产生的激素，随着肥胖而增加，可能是与肥胖相关的心血管风险升高的介质之一。我们和其他人之前已经证明，小鼠瘦素或瘦素受体的完全缺乏对几种血管疾病模型具有保护作用。同样，在人体研究中，瘦素水平升高与心血管风险增加有关。虽然瘦素的唯一相关细胞来源是脂肪细胞，但许多不同的细胞类型表达瘦素受体的信号形式。下丘脑瘦素受体缺乏或完全缺乏瘦素会导致病态肥胖，因此治疗所有瘦素受体或中和所有循环瘦素是不可行的。因此，确定相关的瘦素受体细胞池和负责瘦素在血管疾病中的作用的下游信号通路是重要的。这种竞争性更新的目的是通过小鼠模型确定不同瘦素受体池和信号通路对动脉粥样硬化的影响。瘦素对脂肪组织炎症的影响，这可能是肥胖和血管疾病之间的重要联系，也将被解决。总的来说，这些研究将阐明脂肪组织、炎症和血管疾病之间的联系，并可能发现新的治疗靶点，以降低与肥胖相关的血管风险。公共卫生相关性：肥胖在美国是一种流行病，是动脉粥样硬化性血管疾病（如心肌梗死和中风）并发症的一个重要危险因素。瘦素，一种由脂肪细胞产生的激素，可能是导致与肥胖相关的心血管风险升高的介质之一。通过多种细胞类型表达的瘦素受体传递瘦素信号，尽管负责瘦素对血管终点影响的信号通路和细胞受体池在很大程度上是未知的。本研究的目的是明确瘦素受体介导的信号通路和相关瘦素受体细胞池在动脉粥样硬化中的作用。此外，瘦素对脂肪组织炎症的影响将被解决，因为这可能代表肥胖和血管疾病之间的联系。这些研究的结果可能为降低与肥胖相关的血管风险确定新的靶点。

DESCRIPTION (provided by applicant): Leptin, a hormone produced by the adipocyte, increases with obesity and may be one of the mediators responsible for the elevated cardiovascular risk associated with obesity. We and others have previously shown that complete deficiency of leptin or leptin receptors in mice is protective in several models of vascular disease. Similarly, in human studies, elevated levels of leptin have been associated with increased cardiovascular risk. Although the only relevant cellular source of leptin is the adipocyte, many different cell types express the signaling form of the leptin receptor. Deficiency of hypothalamic leptin receptors or complete deficiency of leptin leads to morbid obesity, therefore therapeutic targeting of all leptin receptors or neutralizing all circulating leptin is not feasible. It is thus important to identify relevant leptin receptor cellular pools and downstream signaling pathways responsible for the effects of leptin in vascular disease. The goal of this competing renewal is to determine the effect of different leptin receptor pools and signaling pathways on atherosclerosis using mouse models. The effect of leptin on inflammation in adipose tissue, which may be an important link between obesity and vascular disease, will also be addressed. Overall, these studies will elucidate links between adipose tissue, inflammation and vascular disease and may uncover novel therapeutic targets to reduce the vascular risk associated with obesity. PUBLIC HEALTH RELEVANCE: Obesity is epidemic in the United States and is a strong risk factor for complications of atherosclerotic vascular disease such as myocardial infarction and stroke. Leptin, a hormone produced by the adipocyte, may be one of the mediators responsible for the elevated cardiovascular risk associated with obesity. Leptin signals via leptin receptors expressed by multiple cell types, although the signaling pathways and cellular receptor pools responsible for the effects of leptin on vascular endpoints is largely unknown. The goal of this proposal is to define the leptin receptor-mediated signaling pathways and relevant leptin receptor cellular pools on atherosclerosis. In addition, the effect of leptin on adipose tissue inflammation will be addressed as this may represent a link between obesity and vascular disease. Results of these studies may identify novel targets for reducing the vascular risk associated with obesity.