Obesity-induced inflammation and insulin resistance by the p62/PKCzeta signaling

描述（由申请人提供）：肥胖是一个迅速增长的公共卫生问题。然而，导致身体脂肪过多以及肥胖与其相关病理学之间联系的潜在机制仍然知之甚少。最近的工作揭示了炎症在慢性代谢疾病（包括肥胖症、2型糖尿病和心血管疾病）的发病机制中的作用。在这方面，巨噬细胞在这些炎症过程中发挥的作用引起了人们的极大兴趣。已知增加的肥胖促进巨噬细胞浸润到脂肪组织中，维持局部炎症并引起胰岛素抵抗。最近的结果表明，巨噬细胞经历了一个从促炎（M1表型）到抗炎（M2表型）的极化转换，以响应脂肪细胞分泌的细胞因子，如IL-4和IL-13和M1和M2之间的平衡决定了最终的炎症结果及其对胰岛素抵抗的影响。然而，有关负责这些炎症网络的不同信号通路及其在体内的相对重要性的关键问题仍未得到解答。因此，研究肥胖期间激活的炎症通路可能是确定糖尿病新治疗靶点的一种有前途的方法。 这项拨款申请的重点是p62/PKC 6信号传导复合物，它是由支架蛋白p62及其PB 1相互作用激酶PKC 6形成的，以及它们在肥胖诱导的炎症和胰岛素抵抗中的潜在作用。它是基于先前的结果表明，基因失活的p62导致迟发性肥胖和胰岛素抵抗，并相关的全身性炎症状态。此外，初步数据显示，PKC 6-/-小鼠也发生迟发性肥胖，这表明p62/PKC 6复合物在控制肥胖和肥胖中的关键作用。重要的是，与同等喂养的WT小鼠相比，高脂饮食喂养的PKC 6-/-小鼠显示出更高的胰岛素抵抗，脂肪组织中的巨噬细胞浸润增加，以及增强的M1炎症反应，尽管体脂含量相同。这些观察结果导致假设PKC 6是巨噬细胞M2极化开关的调节剂。该提案的总体目标是严格检验p62/PKC 6复合物是肥胖期间炎症的关键负调节剂的假设，并确定其在生物体和细胞水平上的作用机制。因此，本项目旨在1）确定p62和PKC 6在巨噬细胞M2极化中的作用，以及2）确定PKC 6和p62在肥胖和肥胖相关炎症中巨噬细胞中的体内作用。这项工作将增加对肥胖诱导的炎症和胰岛素抵抗调节机制的理解，从长远来看，将为开发胰岛素抵抗和2型糖尿病的新的，更具体的治疗方法奠定基础。 公共卫生相关性：慢性炎症与肥胖、胰岛素抵抗和2型糖尿病有因果关系。增加的肥胖促进巨噬细胞浸润到脂肪组织中，形成恶性循环，使炎症持续存在并导致胰岛素抵抗。该项目将确定由p62/Sqstm 1和PKC 6组装的细胞信号复合物如何在体内调节肥胖相关的炎症和胰岛素抵抗，为开发新的，更具体的肥胖疗法奠定基础。

DESCRIPTION (provided by applicant): Obesity is a rapidly growing public health problem. However, the underlying mechanisms that lead to excess body fat and that link obesity to its associated pathologies remain poorly understood. Recent work has revealed a role for inflammation in the pathogenesis of chronic metabolic diseases including obesity, type 2 diabetes and cardiovascular disease. In this regard, there is a significant interest in the role that macrophages play in these inflammatory processes. It is known that increased adiposity promotes macrophage infiltration into adipose tissue, maintaining local inflammation and causing insulin resistance. Recent results suggest that macrophages undergo a polarization switch from pro-inflammatory (M1 phenotype) to anti-inflammatory (M2 phenotype) in response to adipocyte-secreted cytokines such as IL-4 and IL-13 and the balance between M1 and M2 determines the final inflammatory outcome and its impact on insulin resistance. However, key questions concerning the different signaling pathways responsible for these inflammatory networks and their relative importance in vivo remain unanswered. Therefore, investigation of the inflammatory pathways activated during obesity could be a promising approach to identifying novel therapeutic targets for diabetes. This grant application focuses on the p62/PKC6 signaling complex, which is formed by the scaffold protein p62 and its PB1-interacting kinase PKC6, and their potential role in obesity-induced inflammation and insulin resistance. It is based on previous results demonstrating that the genetic inactivation of p62 leads to late-onset obesity and insulin resistance, and to an associated systemic hyperinflammatory state. Moreover, the preliminary data show that PKC6-/- mice also develop late-onset obesity suggesting a critical role of the p62/PKC6 complex in the control of adiposity and obesity. Importantly, high-fat diet-fed PKC6-/- mice displayed higher insulin resistance, increased macrophage infiltration in adipose tissue, and an enhanced M1 inflammatory response as compared to equally fed WT mice, despite equal body fat content. These observations led to the hypothesis that PKC6 is a regulator of the macrophage M2 polarization switch. The overall objective of this proposal is to rigorously test the hypothesis that the p62/PKC6 complex is a critical negative regulator of inflammation during obesity and to determine its mechanism of action at the organismal and cellular levels. Therefore, this project is designed to 1) determine the role of p62 and PKC6 in M2 polarization of macrophages, and 2) to determine the in vivo role of PKC6 and p62 in macrophages in obesity and obesity-associated inflammation. This work will increase understanding of the mechanisms involved in the regulation of obesity-induce inflammation and insulin resistance, and, in the long term, will lay the groundwork for the development of novel, more specific therapies for insulin resistance and type 2 diabetes. PUBLIC HEALTH RELEVANCE: Chronic inflammation is causally linked to obesity, insulin resistance and type 2 diabetes. Increased adiposity promotes macrophage infiltration into adipose tissue creating a vicious cycle that perpetuates inflammation and causes insulin resistance. This project will determine how a cell signaling complex assembled by p62/Sqstm1 and PKC6 regulates obesity-associated inflammation and insulin resistance in vivo, laying the groundwork for the development of novel, more specific therapies for obesity.