A2b Adenosine Receptor Regulation of Metabolic Disease and Inflammation

A2b 腺苷受体对代谢疾病和炎症的调节

• 批准号: 8521741
• 负责人: Anna Eisenstein
• 金额: $ 3.02万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521741
• 关键词: Address; Adenosine; Adenylate Cyclase; Adipocytes; Adipose tissue; Affect; Agonist; American; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Atherosclerosis; Attenuated; Biology; Blood Glucose; Blood Vessels; Cardiovascular Diseases; Cells; Cellular Stress; Cholesterol; Chronic; Collaborations; Data; Dental crowns; Development; Diagnosis; Diet; Disease; Fatty acid glycerol esters; Functional disorder; Glucose; Glucose Intolerance; Homeostasis; Hormones; Human; Hyperglycemia; Hyperlipidemia; Individual; Inflammation; Inflammatory; Injury; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Laboratory Finding; Ligands; Link; Lipids; Liver; Maintenance; Mediating; Mediator of activation protein; Membrane; Membrane Proteins; Mentors; Metabolic; Metabolic Diseases; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Phenotype; Phosphorylation; Plasma; Play; Purinergic P1 Receptors; Receptor Signaling; Regulation; Relative (related person); Reporting; Research; Risk Factors; Role; SRE-1 binding protein; Sampling; Scientist; Signal Transduction; Signaling Molecule; Structure; TNF gene; Testing; Therapeutic; Tissues; Transcription Coactivator; Transgenic Mice; Triad Acrylic Resin; Tumor Necrosis Factor-alpha; United States; Visceral; Wild Type Mouse; bariatric surgery; base; blood glucose regulation; cytokine; diabetic; feeding; human IRS2 protein; human subject; impaired glucose tolerance; insulin secretion; insulin signaling; interest; macrophage; mortality; mouse model; non-diabetic; novel; public health relevance; receptor; receptor expression; response; restoration; subcutaneous; therapeutic target

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.

描述（由申请人提供）：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 的定义是身体无法对血糖水平变化做出反应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。肥胖是 T2D 的一个重要危险因素，它与慢性炎症有关，而且很明显炎症会导致胰岛素抵抗。巨噬细胞是肥胖引起的炎症的关键介质。然而，肥胖、炎症和 T2D 之间的联系机制尚未明确。腺苷是一种可能在这三联体中发挥作用的有趣信号分子，它是一种在细胞应激和炎症后升高的代谢物。通过 A2b 腺苷受体 (A2bAR) 的腺苷信号传导已被证明可以抑制炎症细胞因子的释放。此外，高脂肪、高胆固醇饮食（HFD）会极大地上调A2b腺苷受体（A2bAR）的表达，并且与野生型（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 后还出现葡萄糖清除延迟和胰岛素水平升高的情况。相对于 WT 小鼠，A2bAR KO 小鼠的脂肪组织和肝脏胰岛素信号传导减少。胰岛素受体底物 2 (IRS-2) 是胰岛素信号转导的一种重要介质，它会因炎症细胞因子的作用而减少。在寻找 A2bAR KO 小鼠葡萄糖处理受损的机制时，A2bAR KO 小鼠的肝脏和脂肪组织中 IRS-2 的水平降低。重要的是，在喂食 HFD 的 WT 小鼠（具有 A2bAR 配体）中 A2bAR 的药理学激活可恢复 IRS-2 水平并改善 T2D。重要的是，与瘦受试者相比，肥胖受试者的脂肪组织中 A2bAR 表达升高，并且 A2bAR 表达与 IRS-2 表达密切相关。考虑到 A2bAR 对炎症细胞因子的控制，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 A2bAR、脂肪组织炎症和胰岛素信号传导之间存在联系。通过使用转基因小鼠以及来自糖尿病和非糖尿病肥胖个体的人类脂肪组织，该提案将检验以下新论点：与代谢不健康的人相比，来自肥胖人的代谢健康的脂肪组织具有强烈的 A2bAR 和 IRS-2 表达肥胖人类（目标 1），脂肪和/或巨噬细胞 A2bAR 信号传导有助于 IRS-2 的调节和葡萄糖稳态（目标 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同事、生物化学家兼血管和腺苷生物学专家 Ravid 博士和具有访问权限的临床科学家 Gokce 博士的合作和支持。人类样本和研究人类脂肪组织的专业知识。