A2b Adenosine Receptor Regulation of Metabolic Disease and Inflammation

描述(申请人提供)：II型糖尿病(T2D)是多种疾病的主要危险因素，也是美国发病率和死亡率的重要因素。T2D的定义是，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，身体无法对不断变化的血糖水平做出反应。肥胖是T2D的一个重要危险因素，与慢性炎症有关，而且炎症可以导致胰岛素抵抗，这一点已经变得很清楚。巨噬细胞是肥胖引起的炎症的关键介质。然而，肥胖、炎症和T2D之间的联系机制尚不清楚。一个有趣的信号分子可能在三联体中发挥作用，那就是腺苷，这是一种在细胞应激和炎症后升高的代谢物。腺苷信号通过A2B腺苷受体(A2bAR)被证明可以抑制炎性细胞因子的释放。此外，给予高脂肪、高胆固醇饮食(HFD)的小鼠极大地上调了A2B腺苷受体(A2bAR)的表达，与野生型(WT)小鼠相比，接受HFD的A2bAR KO小鼠血浆细胞因子水平升高。有趣的是，A2bAR KO小鼠在HFD后也有葡萄糖清除延迟和胰岛素水平升高。与WT小鼠相比，A2bAR KO小鼠的脂肪组织和肝脏胰岛素信号转导减少。胰岛素信号转导的一个重要介质，胰岛素受体底物2(IRS-2)，在炎性细胞因子的作用下被降低。为了探索A2bAR KO小鼠糖代谢受损的机制，发现A2bAR KO小鼠肝脏和脂肪组织中IRS-2的水平降低。重要的是，在喂养HFD的WT小鼠(带有A2bAR配体)中，A2bAR的药理激活可以恢复IRS-2水平并改善T2D。重要的是，与瘦身受试者相比，肥胖受试者的脂肪组织中A2bAR的表达升高，并且A2bAR的表达与IRS-2的表达密切相关。考虑到A2bAR对炎性细胞因子的控制，以及这些细胞因子对IRS-2和胰岛素信号的调节，我们假设巨噬细胞A2bAR、脂肪组织炎症和胰岛素信号之间存在联系。随着获得转基因小鼠和糖尿病和非糖尿病肥胖者的人类脂肪组织，这项提案将审查新的论点，即与代谢不健康的肥胖者相比，代谢健康的肥胖者的脂肪组织有A2bAR和IRS-2的强烈表达(目标1)，以及脂肪和/或巨噬细胞A2bAR信号有助于调节IRS-2和葡萄糖稳态(目标2)。拟议中的研究可能会开启新的基于受体的治疗方法，这将得到我在这个项目上的共同导师拉维德博士和戈克斯博士的合作和支持。拉维德博士是一名生物化学家，也是血管和腺苷生物学方面的专家，戈克斯博士是一名临床科学家，可以获得人类样本，并拥有研究人类脂肪组织的专业知识。

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.