The Cholinergic Anti-Inflammatory Pathway in Human Obesity and Insulin Resistance

人类肥胖和胰岛素抵抗中的胆碱能抗炎途径

• 批准号: 7578312
• 负责人: KAREN L TEFF
• 金额: $ 18.52万
• 依托单位: MONELL CHEMICAL SENSES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578312
• 关键词: Acetylcholine; Acute; Address; Adipose tissue; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Biopsy; Blood Pressure; Cardiovascular Diseases; Catecholamines; Cells; Chronic; Crossover Design; Data; Development; Diabetes Mellitus; Disease; Fiber; Future; Human; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interleukin-10; Interleukin-6; Intervention; Investigation; Knowledge; Laboratories; Light; Link; Macrophage Activation; Measures; Mecamylamine; Mediating; Metabolic Diseases; Neuraxis; Nicotine; Nicotinic Receptors; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Physiology; Plasma; Prevalence; Proteins; Regulation; Regulatory Pathway; Resistance development; Role; Sampling; Societies; Sympathetic Nervous System; TNF gene; Testing; Time; Tumor Necrosis Factor Receptor; Vagus nerve structure; adipocyte biology; adiponectin; base; blood glucose regulation; cholinergic; cytokine; heart rate variability; improved; inflammatory marker; insulin sensitivity; interest; intravenous glucose tolerance test; mRNA Expression; macrophage; new therapeutic target; novel; peripheral blood; public health relevance; receptor; resistin; therapeutic target; translational study; urinary

DESCRIPTION (provided by applicant): In light of the increasing prevalence of obesity in our society, elucidation of novel regulatory pathways that could potentially limit the pathophysiological consequences of obesity is of great importance. Elevated inflammatory cytokines are thought to contribute to insulin resistance and the development of chronic metabolic diseases such as type II diabetes, atherosclerosis and cardiovascular disease in obese individuals (1-3). In obese, insulin resistant subjects, macrophage activation increases release of inflammatory cytokines and there is increased macrophage accumulation in adipose tissue (4-7). Exciting new findings demonstrate a link between the central nervous system and regulation of cytokine release from macrophages. Termed the 'cholinergic anti-inflammatory pathway', the data suggest that the release of acetylcholine from vagal efferent fibers inhibits macrophage activation and the subsequent release of inflammatory cytokines (8-12). My laboratory is one of very few to study the role of the vagus nerve in the regulation of glucose homeostasis in humans (13-15). This proposal will apply our knowledge and expertise of vagal physiology to explore for the first time, the role of the nicotinic acetylcholine receptor in vagally mediated inflammatory responses in human obesity. We will test the hypothesis that pharmacological activation of the Nicotinic Acetylcholine Receptor (NAcR) by nicotine will decrease the elevated circulating inflammatory cytokines in obese, insulin resistant humans. The aim of the project is to determine if activation of nicotinic acetylcholine receptors by nicotine administration decreases markers of inflammation. The exploratory aim will evaluate the effect of nicotine administration on insulin sensitivity and sympathetic nervous system activity (SNS) obese insulin resistant subjects. We will use a within subject, crossover design and administer either transdermal nicotine, a known agonist of the nicotinic acetylcholine receptor 1-7 subunit or co-administer transdermal nicotine and the nicotinic acetylcholine receptor antagonist, mecamylamine. During both conditions, we will measure markers of inflammation: IL-6, TNF-1, TNF-1 receptor 2, resistin and the anti- inflammatory marker IL-10. In addition, we will measure insulin sensitivity using the frequently sampled intravenous glucose tolerance test and SNS activity with heart rate variability and urinary catecholamines. This translational study will investigate a previously unexplored mechanism which may contribute to the inflammatory state associated with human insulin resistance. Findings from this study will provide a scientific basis for future translational studies and elucidate a potential therapeutic target for pharmacological intervention. PUBLIC HEALTH RELEVANCE: Elevated levels of cytokines, proteins associated with inflammation, may be responsible for some of the adverse consequences of metabolic diseases such as obesity, type 2 diabetes, cardiovascular disease and atherosclerosis. This study will investigate a novel regulatory pathway regulating cytokine levels in humans. Positive findings would support future investigations for the development of a new therapeutic target to lower cytokine levels in obese individuals.

描述（由申请人提供）：鉴于肥胖症在我们社会中的日益普遍，阐明可能限制肥胖症病理生理后果的新型调控途径非常重要。认为升高的炎性细胞因子有助于胰岛素抵抗和肥胖个体中慢性代谢疾病如II型糖尿病、动脉粥样硬化和心血管疾病的发展（1-3）。在肥胖的胰岛素抵抗受试者中，巨噬细胞活化增加了炎性细胞因子的释放，并且脂肪组织中的巨噬细胞积累增加（4-7）。令人兴奋的新发现证明了中枢神经系统和巨噬细胞释放细胞因子的调节之间的联系。被称为“胆碱能抗炎途径”的数据表明，从迷走神经传出纤维释放乙酰胆碱抑制巨噬细胞活化和随后的炎性细胞因子释放（8-12）。我的实验室是少数几个研究迷走神经在人体葡萄糖稳态调节中的作用的实验室之一（13-15）。这项建议将应用我们的知识和迷走神经生理学的专业知识，探索第一次，在人类肥胖迷走神经介导的炎症反应中的烟碱乙酰胆碱受体的作用。我们将检验以下假设：尼古丁对尼古丁乙酰胆碱受体（NAcR）的药理学激活将降低肥胖、胰岛素抵抗人群中升高的循环炎性细胞因子。该项目的目的是确定尼古丁给药是否会激活烟碱乙酰胆碱受体，从而减少炎症标志物。探索性目的是评价尼古丁给药对胰岛素敏感性和交感神经系统活动（SNS）肥胖胰岛素抵抗受试者的影响。我们将使用受试者内交叉设计，给予经皮尼古丁（一种已知的烟碱乙酰胆碱受体1-7亚基激动剂）或联合给予经皮尼古丁和烟碱乙酰胆碱受体拮抗剂美加明。在这两种情况下，我们将测量炎症标志物：IL-6、TNF-1、TNF-1受体2、IL-10和抗炎标志物IL-10。此外，我们将使用频繁采样的静脉葡萄糖耐量试验和SNS活动与心率变异性和尿儿茶酚胺来测量胰岛素敏感性。这项翻译研究将探讨一个以前未探索的机制，这可能有助于与人类胰岛素抵抗相关的炎症状态。这项研究的结果将为未来的转化研究提供科学依据，并阐明药理学干预的潜在治疗靶点。 公共卫生相关性：细胞因子水平升高，与炎症相关的蛋白质，可能是代谢性疾病如肥胖症，2型糖尿病，心血管疾病和动脉粥样硬化的一些不良后果的原因。本研究将探讨一种新的调节途径，调节人体细胞因子水平。积极的发现将支持未来的研究开发一种新的治疗靶点，以降低肥胖个体的细胞因子水平。