Leptin Action and Macrophages

描述（由申请人提供）：脂肪细胞来源的激素瘦素对脂质代谢的作用被认为在预防组织脂肪毒性和脂质相关胰岛素抵抗的发展中很重要。这在瘦素缺乏的状态下得到了最好的说明，在这种状态下，外源性瘦素的长期服用可以纠正全身血脂异常、脂肪在肝脏等外周组织中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的肥胖（DIO），其特征是与瘦素缺乏条件具有相似的代谢表型，这意味着瘦素作用的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质代谢和胰岛素作用的机制以及瘦素抵抗的机制仍然知之甚少。在过去的十年里，我们的工作主要集中在瘦素对脂质代谢和胰岛素敏感性的作用和机制上，我们最近的工作重点是肝脏，一个调节全身脂质稳态和胰岛素敏感性的中心器官。总之，这些研究确立了瘦素在肝脏氧化和VLDL代谢的急性调节中的新作用，这种作用在肥胖中受损，并确定了这些作用的生化基础。在初步数据中，我们提供的证据表明，许多这些作用是由特化的肝巨噬细胞（Kupffer细胞）介导的。这些数据证明了骨髓细胞在介导瘦素代谢作用中的作用以前未被认识到。当前提案的中心目标是扩展这些观察结果，以解决(i)巨噬细胞在调节瘦素代谢作用中的作用，以及（ii）巨噬细胞瘦素作用的生化和分子机制。在开展这些研究中，我们将增加对瘦素作用机制的理解以及瘦素抵抗对肥胖代谢异常的贡献。为了解决这些问题，我们将利用一系列模型，包括基因操纵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。

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.