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

慢性压力介导胰岛素信号和肠道蠕动与脂肪相关的变化

• 批准号: 7813533
• 负责人: SYLVIE BRADESI
• 金额: $ 49.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813533
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Animal Model; Blood Circulation; Body fat; Body mass index; Cell physiology; Cells; Chronic; Chronic stress; Clinical; Clinical Trials; Corticotropin-Releasing Hormone; Data; Development; Diarrhea; Digestive System Disorders; Disease; Disease Clusterings; Employment Opportunities; Endocrine Glands; Event; Exposure to; Fatty acid glycerol esters; Functional Gastrointestinal Disorders; Functional disorder; Funding; Future; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Physiology; General Population; Glucose; Glucose Intolerance; Homeostasis; Hospitals; Human; Impairment; Inflammatory; Inflammatory disease of the intestine; Insulin; Insulin Resistance; Intestinal Motility; Intra-abdominal; Irritable Bowel Syndrome; Knowledge; Life; Link; Los Angeles; Measures; Mediating; Mesentery; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Modeling; Neuropeptides; Neurotensin; Nociception; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Psychological Stress; Public Health; Rattus; Regulation; Reporting; Research; Research Personnel; Risk Factors; Role; Signal Transduction; Signaling Molecule; Stress; Substance P; Symptoms; Therapeutic; Treatment Cost; United States Department of Veterans Affairs; United States National Institutes of Health; Visceral; Work; abdominal fat; adipocyte biology; base; biological adaptation to stress; cell motility; depression; gastrointestinal; gastrointestinal function; gastrointestinal symptom; instrument; insulin signaling; melanin-concentrating hormone; melanin-concentrating hormone receptor; pre-clinical; programs; public health relevance; receptor; receptor expression; response

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.

描述（由申请人提供）：高达70%的普通人群每年有一种或多种胃肠道疾病，虽然治疗费用极高，但这些症状的病理生理学在很大程度上仍未得到解释。在过去十年中，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，在肥胖中观察到的体脂变化或体重指数的变化（如在患有功能性胃肠疾病的患者中观察到的）与胃肠道症状有关。虽然这些关联的机制尚不清楚，但越来越多的证据清楚地表明，慢性心理压力是这类疾病的关键风险因素。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日期的准确性，开发临床前方法来解决这些条件下压力影响的潜在机制至关重要。在我们的研究小组中，我们最近发现，P物质、促肾上腺皮质激素释放激素和神经紧张素等神经肽既参与应激反应，又参与胃肠运动调节，它们可以刺激人类前脂肪细胞的增殖，表明它们参与脂肪扩张，这是包括II型糖尿病在内的几种疾病状态的一个突出特征。此外，我们已经证明这些神经肽不仅能够诱导脂肪细胞的促炎信号，而且还能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了胰岛素信号的脂肪细胞特异性损伤，这有助于胃肠运动的变化。利用两种经肠易激综合征和抑郁症验证的慢性心理应激大鼠模型，我们拟评估1)慢性应激是否影响内脏脂肪和神经肽的表达，并检查其对脂肪细胞相关胰岛素信号的影响；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胃肠运动的调节。我们期望在本应用中提出的工作将显著增加我们对脂肪组织在与一系列应激相关疾病相关的胃肠道功能改变中的作用的认识，并为未来治疗几种常见应激相关胃肠道疾病的治疗方法提供新的靶点。该提案将建立一个新的合作研究项目，将加州大学洛杉矶分校消化疾病科和洛杉矶退伍军人管理医院胃肠科的应激相关胃肠生理学、病理生理学和运动性、脂肪细胞生物学和代谢、神经肽信号和肠道炎症的互补领域和专业知识汇集在一起。拟议的资金将支持6名研究人员（包括新聘人员），并购买一种新仪器（EchoMRI），该仪器不仅适用于本项目，还适用于加州大学洛杉矶分校正在进行的将肥胖变化与几种疾病状态的病理生理学联系起来的合作研究。此外，所请求的资金专门用于加速获取适用于建立未来合作R01或P01 NIH提案，NIH-私人伙伴关系机会和/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。