Adipokine Signaling in Macrophages

描述（由申请人提供）：在肥胖症中观察到的慢性炎症与医学上重要的并发症的发展有关，特别是动脉粥样硬化、癌症、胰岛素抵抗和非酒精性脂肪肝。巨噬细胞，炎症的关键介质，已被证明有助于显着这些疾病的发展。然而，尽管受到了相当大的关注，但迄今为止关于巨噬细胞通过各种炎症相关脂肪因子（例如，脂联素和脂联素）。巨噬细胞中是否存在多种脂肪因子的共同分子介导物？不同的脂肪因子信号通过不同的途径在巨噬细胞？值得注意的是，我们最近的数据支持这样的观点，即巨噬细胞TORC 2（调节CREB活性的转导子2）通过一种独特的机制控制巨噬细胞活化，该机制涉及TORC 2在特定脂肪因子刺激下的核-胞质穿梭。我们的两个假设是：（i）由脂联素和脂联素介导的脂肪因子信号传导途径会聚于巨噬细胞T0 RC 2;（ii）T0 RC 2的核-胞质穿梭决定巨噬细胞是否被激活，这是控制炎症并影响胰岛素抵抗的病理生理学的事件。这些假设将TORC 2作为将肥胖的全身炎症效应与胰岛素抵抗联系起来的关键参与者。本研究将利用最新的生化和免疫学方法，结合代谢表型分析，对上述假设进行验证，具体目的如下：（1）阐明脂肪因子调节巨噬细胞TORC 2活性的信号通路，重点是鉴定应答性激酶和磷酸酶;（2）在表达组成型活性TORC 2突变体的巨噬细胞特异性转基因小鼠模型中验证TORC 2在炎症和胰岛素抗性中的生理重要性;（3）进一步阐明TORC 2在使用骨髓移植产生的功能丧失TORC 2小鼠模型中的炎症和胰岛素抵抗中的作用。假设的证实将确定巨噬细胞的脂肪因子信号传导和导致巨噬细胞活化的细胞内事件所需的关键分子。与人类健康的相关性：阐明这一信号通路将为肥胖诱导的胰岛素抵抗及相关慢性疾病的发生奠定基础。它将提供一个或多个候选目标，用于慢性炎症加重的疾病的药物干预，并可能建立TORC 2或其相互作用伙伴作为慢性炎症发作的早期标志物。公共卫生相关性：该提案研究了肥胖及其相关炎症性疾病（包括动脉粥样硬化、癌症和糖尿病）背景下巨噬细胞中脂肪因子信号传导的分子基础。阐明这一信号通路将为肥胖诱导的胰岛素抵抗及相关慢性疾病的发生奠定基础。它将提供一个或多个候选目标，用于慢性炎症加重的疾病的药物干预，并可能建立TORC 2或其相互作用伙伴作为慢性炎症发作的早期标志物。

DESCRIPTION (provided by applicant): Chronic inflammation observed in obesity has been implicated in the development of medically important complications, particularly atherosclerosis, cancer, insulin resistance and non-alcoholic fatty liver disease. Macrophages, key mediators of inflammation, have been shown to contribute significantly to the development of these disorders. Despite considerable attention, however, there is little information thus far on the mechanism through which macrophages are differentially regulated by various inflammation- related adipokines (e.g., adiponectin and resistin) secreted by adipocytes. Is there a common molecular mediator in macrophages for various adipokines? Do various adipokines signal through distinctive pathways in macrophages? Remarkably, our recent data support the notion that macrophage TORC2 (for Transducers Of Regulated CREB activity 2) controls macrophage activation via a unique mechanism, involving nuclear-cytosolic shuttling of TORC2, upon stimulation by specific adipokines. Our two hypotheses are: (i) the adipokine signaling pathways mediated by adiponectin and resistin converge on macrophage TORC2; (ii) nuclear-cytosolic shuttling of TORC2 determines whether macrophages are activated, an event which controls inflammation and influences the pathophysiology of insulin resistance. These hypotheses place TORC2 as the key player that links systemic inflammatory effects of obesity to insulin resistance. Using the state-of-art biochemical and immunological approaches together with metabolic phenotyping, we will test these hypotheses with the following three Specific Aims: (1) to delineate the signaling pathway by which adipokines regulate TORC2 activity in macrophages, focusing on identification of the responsive kinase and phosphatase; (2) to validate the physiological importance of TORC2 in inflammation and insulin resistance in a macrophage-specific transgenic mouse model expressing a constitutively active TORC2 mutant; (3) to further elucidate the role of TORC2 in inflammation and insulin resistance in a loss-of-function TORC2 mouse model generated using bone marrow transplantation. Confirmation of the hypotheses will identify key molecules required for adipokine signaling of the macrophages and intracellular events leading to macrophage activation. Relevance to human health: Delineating the signaling pathway(s) will establish a pivotal mechanism for obesity- induced insulin resistance and related chronic diseases. It will provide one or more candidate targets for drug intervention in conditions exacerbated by chronic inflammation, and possibly establish TORC2 or its interacting partners as early markers of the onset of chronic inflammation. PUBLIC HEALTH RELEVANCE: This proposal investigates the molecular basis of adipokine signaling in macrophages in the context of obesity and its-related inflammatory disorders including atherosclerosis, cancer and diabetes. Delineating the signaling pathway(s) will establish a pivotal mechanism for obesity-induced insulin resistance and related chronic diseases. It will provide one or more candidate targets for drug intervention in conditions exacerbated by chronic inflammation, and possibly establish TORC2 or its interacting partners as early markers of the onset of chronic inflammation.