TPL2: A Central Node in Obesity-Associated Inflammation and Metabolic Disorders

描述(申请人提供)：肥胖是2型糖尿病(T2 DM)的主要独立危险因素，肥胖促进慢性巨噬细胞介导的脂肪组织炎症，导致脂肪细胞释放更多游离脂肪酸和甘油三酯异位堆积。这些与肥胖相关的炎症增加和脂质稳态改变单独或联合会促进胰岛素抵抗(IR)、2型糖尿病及其合并症的发生。这项拨款申请中概述的研究将测试关于肿瘤进展基因2(Tpl2)的作用如何促进肥胖相关的炎症和IR的假说。Tpl2是炎症信号的“上游”介体。TPL2是一种丝氨酸/苏氨酸激酶，位于IKK-2的下游，据报道可以激活MAPK(ERK，JNK)，上调促炎细胞因子(如，TNF-1，IL-12)的产生。重要的是，ERK、JNK和促炎细胞因子直接参与了脂肪分解、肝脏脂肪变性和/或肥胖的胰岛素信号受损。Tpl2在肥胖相关炎症和IR中的作用尚不清楚。我们假设肥胖状态下的Tpl2活性激活MAPK通路，诱导促炎细胞因子的表达，从而促进糖/胰岛素稳态改变和肝脏脂肪变性。初步研究表明，与野生型(WT)小鼠相比，高脂饮食(HFD)喂养的Tpl2基因敲除(TPLKO)小鼠可显著防止1)巨噬细胞介导的脂肪组织炎症，2)脂肪和肝脏诱导IR促进炎症介质(如肿瘤坏死因子-1，IL-12)，3)肝脏生脂和生糖基因表达失调，4)肝脏脂肪变性和5)血糖-胰岛素稳态改变。这些观察有力地表明，Tpl2是肥胖症的炎症和代谢并发症中的一个新的和重要的主角，这些并发症使个体易于发生T2 DM。在这笔赠款中，我们将完成以下具体目标：1)在两种不同的肥胖模型中，对TPLKO小鼠的炎症和代谢表型进行详细的分析：1)高脂饮食(HFD)和2)ob/ob小鼠，一种小鼠肥胖的遗传模型。2)确定Tpl2在造血(免疫)和非造血细胞及组织中在介导肥胖相关的炎症和代谢紊乱中的作用。3)确定Tpl2在调节脂肪细胞和巨噬细胞中的肿瘤坏死因子-1和脂肪酸诱导的信号通路中的作用。这些研究将阐明Tpl2在肥胖相关的炎症和代谢紊乱中的核心作用。公共卫生相关性：肥胖与患糖尿病和肝病的风险增加有关。在这项拨款申请中，我们将确定一种名为Tpl2的蛋白质的特定作用，我们假设Tpl2是肥胖者中导致糖尿病和肝脏疾病发展的关键因素。了解Tpl2在肥胖中的作用可能会为糖尿病等肥胖并发症带来潜在的新疗法。

DESCRIPTION (provided by applicant): Obesity is a major independent risk factor for type 2 diabetes mellitus (T2DM), obesity promotes chronic macrophage-mediated adipose tissue inflammation, resulting in increased release of free fatty acids from adipocytes and ectopic accumulation of triglyceride. Alone and in combination, these obesity-associated increases in inflammation and altered lipid homeostasis promote insulin resistance (IR), type 2 diabetes mellitus and its comorbidities. Studies outlined in this grant application will test hypotheses concerning how the actions of Tumor Progression Locus 2 (TPL2), an 'upstream' mediator of inflammatory signaling, promote obesity-associated inflammation and IR. TPL2 is a serine/threonine kinase, located downstream of IKK-2 and reported to activate MAP Kinases (MAPK) (ERK, JNK) and upregulate pro-inflammatory cytokine (e.g., TNF-1, IL-12) production. Importantly, ERK, JNK and pro-inflammatory cytokines are directly implicated in the dysregulated lipolysis, hepatic steatosis and/or compromised insulin signaling of obesity. The role of TPL2 in obesity-associated inflammation and IR is unknown. We hypothesize that TPL2 activity in the obese state activates MAPK pathways and induces pro-inflammatory cytokine expression, thereby promoting altered glucose/insulin homeostasis and hepatic steatosis. Preliminary Studies demonstrate that relative to wild-type (WT) mice, TPL2 knockout (TPLKO) mice fed a high fat diet (HFD) were substantially protected from 1) macrophage-mediated adipose tissue inflammation, 2) adipose and hepatic induction of IR-promoting inflammatory mediators (e.g., TNF-1, IL-12), 3) dysregulated hepatic lipogenic and gluconeogenic gene expression, 4) hepatic steatosis and 5) alterations in glucose-insulin homeostasis. These observations strongly suggest that TPL2 is a novel and important protagonist in the inflammatory and metabolic complications of obesity that predispose individuals to the onset of T2DM. In this grant we will complete the following Specific Aims: 1) To conduct a detailed analysis of the inflammatory and metabolic phenotype of TPLKO mice in two separate models of obesity: 1) high fat diet (HFD) and 2) the ob/ob mouse, a genetic model of murine obesity. 2) To determine the role of TPL2 in hematopoietic (immune) and non-hematopoietic cells and tissues in mediating obesity-associated inflammation and metabolic disorders. 3) To determine the role of TPL2 in regulating TNF-1 and fatty acid-induced signaling pathways in adipocytes and macrophages. These studies will elucidate the central role of TPL2 in obesity-associated inflammation and metabolic disorders. PUBLIC HEALTH RELEVANCE: Obesity is associated with increased risk of developing diabetes and liver disease. In this grant application we will determine the specific role of a protein, called TPL2, that we hypothesize is a critical factor in obese individuals that contributes to the development of diabetes and liver disease. Understanding the role of TPL2 in obesity may lead to potential new therapies for the complications of obesity such as diabetes.