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，对美国的发病率和死亡率的重要促进因素是由于身体无法响应对glucose调节性激素降低的血糖水平的响应而无法响应的，因此身体无法响应血糖水平的变化。肥胖症是T2D的重要危险因素，与慢性炎症有关，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体。但是，连接肥胖，炎症和T2D的机制尚未明确确定。可能在该三合会中起作用的一个有趣的信号分子是腺苷，腺苷是一种代谢产物，在细胞应激和炎症之后升高。通过A2B腺苷受体（A2BAR）的腺苷信号传导已显示可抑制炎性细胞因子的释放。此外，与野生型（WT）小鼠相比，高脂肪高胆固醇饮食（HFD）极大地上调了A2B腺苷受体（A2BAR）和患有HFD的A2BAR KO小鼠的表达，其血浆细胞因子水平升高。有趣的是，A2BAR KO小鼠在HFD之后还延迟了葡萄糖清除率和增强的胰岛素水平。相对于WT小鼠，A2BAR KO小鼠中脂肪组织和肝胰岛素信号传导降低。胰岛素受体底物2（IRS-2）的一种重要的胰岛素信号转导介质通过炎症细胞因子的作用降低。为了寻找A2BAR KO小鼠中葡萄糖处理受损的机制，在A2BAR KO小鼠的肝脏和脂肪组织中，IRS-2的水平降低了。重要的是，在WT小鼠中A2BAR的药理激活（具有A2BAR配体）喂养A HFD会恢复IRS-2水平并改善T2D。重要的是，与精益受试者相比，来自肥胖人类受试者的脂肪组织中A2BAR表达升高，而A2BAR表达与IRS-2表达密切相关。考虑到A2BAR控制炎症细胞因子，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传导之间存在联系。 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稳态（目标2）。拟议的研究可能会开放新的基于受体的治疗方法，这是由我的合作者在该项目上的合作和支持的促进的，是血管和腺苷生物学的生物化学家兼专家Ravid博士，以及临床医生Gokce博士，临床医生，一名访问人类样本的临床医生，并在研究人类脂肪组织中的专业知识。