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

描述(申请人提供)：鉴于肥胖在我们的社会中日益普遍，阐明可能限制肥胖的病理生理后果的新的调控途径是非常重要的。在肥胖者中，炎性细胞因子的升高被认为是导致胰岛素抵抗和慢性代谢性疾病发展的原因，如II型糖尿病、动脉粥样硬化和心血管疾病(1-3)。在肥胖、胰岛素抵抗的受试者中，巨噬细胞的激活增加了炎性细胞因子的释放，并增加了脂肪组织中巨噬细胞的聚集(4-7)。令人兴奋的新发现表明，中枢神经系统和巨噬细胞释放细胞因子的调节之间存在联系。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可以抑制巨噬细胞的激活和随后炎性细胞因子的释放(8-12)。我的实验室是极少数研究迷走神经在调节人类葡萄糖稳态中的作用的实验室之一(13-15)。这项建议将应用我们迷走神经生理学的知识和专业知识，首次探索烟碱型乙酰胆碱受体在迷走神经介导的炎症反应中在人类肥胖中的作用。我们将验证这样一种假设，即尼古丁对烟碱型乙酰胆碱受体(NACR)的药理激活将减少肥胖、胰岛素抵抗的人类循环中升高的炎性细胞因子。该项目的目的是确定尼古丁注射激活烟碱型乙酰胆碱受体是否会减少炎症标志物。本研究旨在评估尼古丁对肥胖胰岛素抵抗受试者的胰岛素敏感性和交感神经系统活动的影响。我们将采用受试者内交叉设计，要么经皮给药尼古丁，一种已知的烟碱型乙酰胆碱受体1-7亚单位激动剂，要么联合经皮给药尼古丁和烟碱型乙酰胆碱受体拮抗剂甲戊胺。在这两种情况下，我们将检测炎症标志物：IL-6、肿瘤坏死因子-1、肿瘤坏死因子-1受体2、抵抗素和抗炎标志物IL-10。此外，我们还将使用频繁采样的静脉葡萄糖耐量试验以及心率变异性和尿儿茶酚胺的SNS活动来测量胰岛素敏感性。这项翻译研究将探索一种以前未被探索的机制，该机制可能导致与人类胰岛素抵抗相关的炎症状态。本研究的结果将为未来的转译研究提供科学依据，并阐明药物干预的潜在治疗靶点。 公共卫生相关性：细胞因子水平升高，即与炎症相关的蛋白质，可能是肥胖症、2型糖尿病、心血管疾病和动脉粥样硬化等代谢性疾病的一些不良后果的原因。这项研究将探索一种新的调节人类细胞因子水平的调节途径。积极的发现将支持未来开发降低肥胖者细胞因子水平的新治疗目标的研究。

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.