A2b Adenosine Receptor Regulation of Metabolic Disease and Inflammation

描述（由申请人提供）：II型糖尿病（T2 D）是多种疾病的主要风险因素，是美国发病率和死亡率的重要因素。T2 D定义为由于组织对葡萄糖调节激素、胰岛素的反应性降低和/或胰岛素分泌不足，导致身体无法对血糖水平变化做出反应。肥胖是T2 D的一个重要风险因素，与慢性炎症相关，并且已经清楚炎症可以导致胰岛素抵抗。巨噬细胞是肥胖引起的炎症的关键介质。然而，连接肥胖、炎症和T2 D的机制尚未明确。一个有趣的信号分子可能在这三个方面发挥作用，是腺苷，一种代谢产物，在细胞应激和炎症后升高。通过A2 b腺苷受体（A2 bAR）的腺苷信号传导已显示抑制炎性细胞因子的释放。此外，施用高脂肪、高胆固醇饮食（HFD）极大地上调A2 b腺苷受体（A2 bAR）的表达，并且与野生型（WT）小鼠相比，经受HFD的A2 bAR KO小鼠具有升高的血浆细胞因子水平。有趣的是，A2 bAR KO小鼠在HFD后也具有延迟的葡萄糖清除和增加的胰岛素水平。相对于WT小鼠，A2 bAR KO小鼠的脂肪组织和肝脏胰岛素信号传导减少。胰岛素信号传导的一种重要介质，胰岛素受体底物2（IRS-2），通过炎性细胞因子的作用而减少。在寻找A2 bAR KO小鼠中葡萄糖处理受损的机制时，显示A2 bAR KO小鼠的肝脏和脂肪组织中IRS-2水平降低。重要的是，在喂食HFD的WT小鼠（具有A2 bAR配体）中A2 bAR的药理学活化恢复IRS-2水平并改善T2 D。重要的是，与瘦型受试者相比，在来自肥胖人类受试者的脂肪组织中A2 bAR表达升高，并且A2 bAR表达与IRS-2表达强烈相关。考虑到A2 bAR对炎性细胞因子的控制，以及这些细胞因子对IRS-2和胰岛素信号传导的调节，我们假设巨噬细胞A2 bAR、脂肪组织炎症和胰岛素信号传导之间存在联系。通过获得转基因小鼠和来自糖尿病和非糖尿病肥胖个体的人脂肪组织，该提议将研究新的论点，即与代谢不健康的肥胖人相比，来自肥胖人的代谢健康的脂肪组织具有A2 bAR和IRS-2的强表达（目的1），并且脂肪和/或巨噬细胞A2 bAR信号传导有助于IRS-2的调节和葡萄糖稳态（Aim 2）。拟议的研究可能会开辟新的基于受体的治疗方法，这得益于我在该项目上的共同导师Ravid博士（生物化学家和血管和腺苷生物学专家）和Gokce博士（临床科学家，可获得人体样本和研究人体脂肪组织的专业知识）的合作和支持。

DESCRIPTION (provided by applicant): Type II diabetes mellitus (T2D) is a major risk factor for multiple diseases and a significant contributor to morbidity and mortality in the United States T2D is defined by an inability of the body to respond to changing blood glucose levels due to reduced responsiveness of tissues to the glucose regulatory hormone, insulin, and/or an insufficient secretion of insulin. Obesity, a significant risk factor for T2D, is associated with chronic inflammation and it has become clear that inflammation can contribute to insulin resistance. The macrophage is a key mediator of obesity-induced inflammation. However, the mechanism connecting obesity, inflammation and T2D is not clearly established. One interesting signaling molecule that may play a role in this triad is adenosine, a metabolite that is elevated following cellular stress and inflammation. Adenosine signaling through the A2b adenosine receptor (A2bAR) has been shown to dampen the release of inflammatory cytokines. Furthermore, administration of a high fat, high cholesterol diet (HFD) vastly upregulates the expression of the A2b adenosine receptor (A2bAR), and A2bAR KO mice subjected to HFD have elevated plasma cytokine levels compared to wild type (WT) mice. Intriguingly, A2bAR KO mice also have delayed glucose clearance and augmented insulin levels following HFD. Adipose tissue and liver insulin signaling is reduced in A2bAR KO mice relative to WT mice. One important mediator of insulin signaling, the insulin receptor substrate 2 (IRS-2), is reduced by the action of inflammatory cytokines. In search for a mechanism of impaired glucose handling in A2bAR KO mice, the level of IRS-2 was shown to be decreased in the liver and adipose tissue of A2bAR KO mice. Importantly, pharmacological activation of A2bAR in WT mice (with an A2bAR ligand) fed a HFD restores IRS-2 levels and ameliorates T2D. Importantly, A2bAR expression is elevated in adipose tissue from obese human subjects as compared to lean subjects and A2bAR expression correlates strongly with IRS-2 expression. Considering the control of inflammatory cytokines by A2bAR, and the regulation of IRS-2 and insulin signaling by these cytokines, we hypothesize a link between macrophage A2bAR, adipose tissue inflammation, and insulin signaling. With access to genetically modified mice and to human adipose tissue from diabetic and non-diabetic obese individuals, this proposal will examine the novel contentions that metabolically healthy adipose tissue from obese humans have a strong expression of A2bAR and IRS-2 as compared to metabolically unhealthy obese humans (Aim 1), and that fat and/or macrophage A2bAR signaling contributes to regulation of IRS-2 and to glucose homeostasis (Aim 2). Proposed studies might open new receptor-based therapeutic approaches, facilitated by the collaboration and support of my co- mentors on this project, Dr. Ravid, a Biochemist and expert in vascular and adenosine biology, and Dr. Gokce, a Clinician Scientist with access to human samples and expertise in studying human adipose tissue.