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

描述（由申请人提供）：鉴于肥胖在我们社会的日益普遍，阐明可能限制肥胖病理生理后果的新调控途径是非常重要的。炎症细胞因子升高被认为有助于胰岛素抵抗和慢性代谢性疾病的发展，如肥胖个体的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症细胞因子的释放，并且脂肪组织中巨噬细胞的积累增加（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，迷走神经传出纤维释放乙酰胆碱抑制巨噬细胞的激活和随后的炎症细胞因子的释放（8-12）。我的实验室是研究迷走神经在人类葡萄糖稳态调节中的作用的极少数实验室之一（13-15）。这一建议将运用我们在迷走神经生理学方面的知识和专业知识，首次探索烟碱乙酰胆碱受体在迷走神经介导的人类肥胖炎症反应中的作用。我们将验证尼古丁对尼古丁乙酰胆碱受体（nictinic Acetylcholine Receptor, NAcR）的药理激活将降低肥胖、胰岛素抵抗人群中升高的循环炎症细胞因子的假设。该项目的目的是确定尼古丁给药激活尼古丁乙酰胆碱受体是否会减少炎症标志物。本研究旨在探讨尼古丁对肥胖胰岛素抵抗者胰岛素敏感性和交感神经系统活性的影响。我们将使用受试者内交叉设计，并给药透皮尼古丁，一种已知的尼古丁乙酰胆碱受体1-7亚基激动剂，或同时给药透皮尼古丁和尼古丁乙酰胆碱受体拮抗剂甲胺。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，抵抗素和抗炎标志物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。这项转化性研究将探讨一个以前未被探索的机制，它可能有助于与人类胰岛素抵抗相关的炎症状态。本研究结果将为今后的转化研究提供科学依据，并阐明药物干预的潜在治疗靶点。

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.