Chronic stress mediates fat-related changes in insulin signaling and gut motility

描述（由申请人提供）：高达70%的一般人群每年有一个或多个胃肠道投诉，虽然产生极高的治疗费用，这些症状的病理生理学仍然在很大程度上无法解释。在过去的十年中，越来越多的研究表明胃肠道症状与代谢功能改变相关的疾病（如胰岛素抵抗或代谢综合征）之间存在关联。此外，在肥胖症中观察到的体脂变化或体重指数变化（如在患有功能性胃肠道疾病的患者中观察到的）与胃肠道症状相关。虽然这些关联背后的机制尚不清楚，但越来越多的证据清楚地表明，慢性心理压力是这一组疾病的一个关键风险因素。然而，慢性应激、代谢途径改变和胃肠道功能障碍之间的联系尚未得到研究。鉴于在非实验性临床环境中缺乏生活事件报告和约会的准确性，开发临床前方法来解决这些条件下压力影响的机制至关重要。在我们的小组中，我们最近发现，神经肽，如P物质，促肾上腺皮质激素释放激素和神经降压素，参与应激反应和胃肠动力的调节，可以刺激人类前脂肪细胞的增殖，这表明它们参与脂肪扩张，这是几种疾病状态的一个突出特征，包括II型糖尿病。此外，我们已经证明了这些神经肽不仅能够诱导脂肪细胞中的促炎信号传导，而且能够影响它们对胰岛素的反应。我们的一般假设是，应激诱导的内脏脂肪组织内神经肽水平的变化触发脂肪细胞特异性胰岛素信号传导障碍，这有助于胃肠动力的变化。使用2种慢性心理应激大鼠模型验证肠易激综合征和抑郁症，我们建议评估1）慢性应激是否影响内脏肥胖和神经肽的表达，并检查它们对脂肪细胞相关胰岛素信号传导的影响; 2）慢性心理应激在葡萄糖耐受不良和胰岛素抵抗发展中的作用，并确定这些反应是否参与了调节胃肠运动。我们预计，在本申请中提出的工作将显着增加我们的知识的作用，脂肪组织的胃肠道功能的改变与一组应激相关的疾病，并提供新的目标，为未来的治疗方法，用于治疗几种常见的应激相关的胃肠道疾病。这项建议将建立一个新的合作研究计划，汇集互补领域和专业知识的压力相关的胃肠道生理学和病理生理学和运动，脂肪细胞生物学和代谢，神经肽信号和肠道炎症的基础上消化疾病在加州大学洛杉矶分校和GI单位在洛杉矶退伍军人管理医院。拟议的资金将支持6名研究人员（包括新员工）和购买一种新仪器（EchoMRI），该仪器不仅适用于该项目，而且适用于加州大学洛杉矶分校校园正在进行的合作研究，将肥胖的变化与几种疾病状态的病理生理学联系起来。此外，所申请的资金专门用于加速获得适用于建立未来合作R 01或P01 NIH提案，NIH-私人合作机会和/或临床试验的概念验证数据，这些数据将迅速产生额外的就业机会。 公共卫生相关性：在临床环境中，包括代谢综合征、II型糖尿病、肥胖症在内的一系列疾病与胃肠道症状的发生之间存在强相关性。虽然慢性心理压力已被描述为这些疾病的关键风险因素，但慢性压力，与代谢途径改变相关的脂肪细胞反应和胃肠道功能障碍之间的联系尚未研究。我们的研究，使用慢性心理压力的动物模型，提出填补这一空白。

DESCRIPTION (provided by applicant): Up to 70% of the general population has one or more gastrointestinal complaints annually, and while incurring extremely high costs for treatment, the pathophysiology of these symptoms remains largely unexplained. In the last decade, an increasing number of studies have demonstrated an association between gastrointestinal symptoms and diseases related to altered metabolic functions (such as insulin resistance or metabolic syndrome). Furthermore, changes in body fat observed in obesity, or changes in body mass index (as observed in patients suffering from functional gastrointestinal disorders) have been associated with gastrointestinal symptoms. While the mechanisms underlying these associations are unknown, accumulating evidence clearly demonstrates chronic psychological stress as a key risk factor in this cluster of diseases. Yet, the link(s) between chronic stress, altered metabolic pathways and gastrointestinal dysfunctions has not been investigated. In view of the lack of accuracy of life events reporting and dating in non experimental clinical settings, it is critical to develop preclinical approaches to address the mechanisms underlying the effect of stress in these conditions. In our group, we recently showed that neuropeptides such as substance P, corticotropin-releasing hormone, and neurotensin, that are involved in both the stress response and the modulation of gastrointestinal motility, can stimulate proliferation in human preadipocytes, suggesting their participation in fat expansion, a prominent feature of several disease states, including type II diabetes. In addition, we have demonstrated the ability of these neuropeptides not only to induce pro-inflammatory signaling in adipocytes, but also to affect their response to insulin. Our general hypothesis is that stress- induced changes in neuropeptides levels within visceral adipose tissue trigger adipocyte specific impairment of insulin signaling, which contributes to changes in gastrointestinal motility. Using 2 rat models of chronic psychological stress validated for irritable bowel syndrome and depression, we propose to evaluate 1) whether chronic stress affects visceral adiposity and the expression of neuropeptides and examine their effect on adipocytes-associated insulin signaling and 2) the role of chronic psychological stress in the development of glucose intolerance and insulin resistance and determine whether these responses are involved in the modulation of gastrointestinal motility. We anticipate that the work proposed in this application will significantly increase our knowledge on the role of adipose tissue in alterations of gastrointestinal functions associated with a cluster of stress-related diseases and provide new targets for future therapeutic approaches for the treatment of several common stress-associated gastrointestinal diseases. This proposal will establish a new Collaborative Research Program by bringing together complementary fields and expertise of stress-related gastrointestinal physiology and pathophysiology and motility, adipocyte biology and metabolism, neuropeptide signaling and intestinal inflammation based at the Division of Digestive Diseases at UCLA and the GI unit at the Los Angeles Veterans Administration Hospital. The proposed funding will support 6 researchers (including new hires) and the acquisition of a new instrument (EchoMRI) that will be applicable not only to this project, but to ongoing collaborative research in the UCLA campus linking changes in adiposity with the pathophysiology of several disease states. Moreover, the requested funds are specifically aimed at accelerating the acquisition of proof-of-concept data suitable for establishing future collaborative R01 or P01 NIH proposals, NIH-Private Partnership Opportunities and/or clinical trials that will rapidly generate additional employment opportunities. PUBLIC HEALTH RELEVANCE: A strong association between a cluster of diseases, including metabolic syndrome, type II diabetes, obesity, and the development of gastrointestinal symptoms has been consistently described in clinical settings. While chronic psychological stress has been described as a key risk factor in these conditions, the link between chronic stress, adipocyte responses associated with altered metabolic pathways, and gastrointestinal dysfunctions has not been investigated. Our study, using animal models of chronic psychological stress, proposes to fill this gap.