Leptin Action and Macrophages

描述(由申请人提供)：脂肪细胞衍生的激素瘦素对脂类代谢的作用被认为在防止组织脂毒性和脂类相关的胰岛素抵抗的发展中具有重要作用。这在瘦素缺乏的状态下表现得最好，长期服用外源性瘦素可以纠正全身性血脂异常、肝脏等外周组织中脂肪的过度储存以及与此相关的胰岛素抵抗。此外，瘦素抵抗状态，如人类肥胖和饮食诱导肥胖(DIO)，其代谢表型与瘦素缺乏状态相似，提示瘦素作用丧失在肥胖代谢异常的发病机制中起作用。然而，尽管取得了一些进展，但我们对瘦素调节脂代谢和胰岛素作用的机制以及瘦素抵抗的机制仍知之甚少。在过去的十年里，我们的工作集中在瘦素对脂代谢和胰岛素敏感性的影响和机制上，最近的工作集中在肝脏，这是调节全身脂平衡和胰岛素敏感性的中心器官。简而言之，这些研究确立了瘦素在急性调节肝脏氧化和极低密度脂蛋白代谢中的新作用，以及在肥胖中受损的作用，并确定了这些作用的生化基础。在初步数据中，我们提出的证据表明，这些效应中的许多是由特化的肝巨噬细胞(Kupffer细胞)介导的。这些数据表明，髓系细胞在调节瘦素的代谢活动中扮演了以前未被认识到的角色。本提案的中心目标是扩展这些观察，以解决(I)巨噬细胞在介导瘦素代谢活动中的作用，以及(Ii)巨噬细胞瘦素作用的生化和分子机制。通过开展这些研究，我们将加深对瘦素作用机制的了解，以及瘦素抵抗在肥胖代谢异常中的作用。为了解决这些问题，我们将利用一系列模型，包括基因操纵的小鼠和基于细胞的共培养系统，以及包括代谢、生化和分子分析在内的方法。 与公共卫生相关：在西方社会，肥胖和II型糖尿病(糖尿病)以及随之而来的代谢异常(包括血脂异常、胰岛素抵抗和脂肪变性)的患病率已接近流行水平。瘦素是一种脂肪细胞激素，已被认为在这些过程的调节中发挥作用。因此，了解瘦素的作用机制和靶点对于描述糖尿病的发病机制和开发潜在的治疗方法至关重要。本提案中详细说明的工作计划的完成有可能对这两个领域产生影响。

DESCRIPTION (provided by applicant): The actions of the adipocyte-derived hormone leptin on lipid metabolism are proposed to be important in preventing the development of tissue lipotoxicity and lipid-related insulin resistance. This is best illustrated in leptin-deficient states, where chronic administration of exogenous leptin corrects systemic dyslipidemia, excessive storage of lipid in peripheral tissues such as the liver, and insulin resistance associated with this condition. Furthermore, states of leptin resistance such as human obesity and diet-induced obesity (DIO) are characterized by a similar metabolic phenotype to leptin deficient conditions, implicating a role for a loss of leptin action in the pathogenesis of the metabolic abnormalities of obesity. However, despite some progress, our understanding of the mechanisms of leptin regulation of lipid metabolism and insulin action, and the mechanisms of leptin resistance remains poor. Our work over the last decade has focused on the effects and mechanisms of leptin action on lipid metabolism and insulin sensitivity, with our recent work focusing on liver, a central organ in the regulation of whole-body lipid homeostasis and insulin sensitivity. In brief these studies established a novel role for leptin in the acute regulation of hepatic oxidative and VLDL metabolism, effects that are impaired in obesity, and identified the biochemical basis for these effects. In preliminary data, we present evidence that many of these effects are mediated by specialized liver macrophages (Kupffer cells). These data demonstrate a previously unappreciated role for myeloid cells in mediating the metabolic actions of leptin. The central objective of the current proposal is to extend these observations to address (i) the role of macrophages in mediating the metabolic actions of leptin, and (ii) the biochemical and molecular mechanisms of macrophage leptin action. In undertaking these studies, we will increase our understanding of the mechanisms of leptin action and the contribution of leptin resistance to the metabolic abnormalities of obesity. To address these questions we will utilize a range of models, including genetically manipulated mice and cell based co-culture systems, and approaches, including metabolic, biochemical, and molecular analysis. PUBLIC HEALTH RELEVANCE: The prevalence of obesity and type II diabetes (diabesity), and attendant metabolic abnormalities including dyslipidemia, insulin resistance, and steatosis has reached near epidemic proportions in western societies. Leptin, the adipocyte hormone, has been proposed to play a role in the regulation of each of these processes. Thus, an understanding of the mechanisms and targets of leptin action are critical to delineating the pathogenesis of, and the development of potential treatments for, diabesity. The completion of the work program detailed in this proposal has the potential to influence both of these areas.