Role of the GI lymphatic system in hormonal signaling and nutrient metabolism

胃肠道淋巴系统在激素信号传导和营养代谢中的作用

• 批准号: 10164765
• 负责人: Min Liu
• 金额: $ 59.39万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164765
• 关键词: Address; Affect; Area; Blood Circulation; Chronic; Chylomicrons; Conscious; Corticosterone; Data; Dependence; Dextrins; Dietary Fats; Dose; Ensure; Enterocytes; Enteroendocrine Cell; Estrous Cycle; Female; Fistula; Food; Gastrointestinal tract structure; Glucocorticoids; Glucose; Health; Hepatic; Hormone secretion; Hormones; Impairment; Inflammation Mediators; Ingestion; Insulin; Intestines; Knowledge; Lamina Propria; Lipids; Liver; Lymph; Lymphatic; Lymphatic System; Macronutrients Nutrition; Mediating; Metabolic; Metabolic hormone; Modeling; Mucous Membrane; Muscle; Nutrient; Organ; Ovarian hormone; Peripheral; Physiological; Physiology; Plasma; Process; Proteins; Radiolabeled; Rattus; Request for Applications; Research; Role; Sex Differences; Signal Transduction; Source; Specificity; Stomach; Testing; Tracer; Triglycerides; Vagus nerve structure; absorption; cell type; cholesterol absorption; energy balance; ghrelin; glucagon-like peptide 1; glucose tolerance; glucose uptake; hormonal signals; hypothalamic-pituitary-adrenal axis; improved; in vivo; incretin hormone; inflammatory disease of the intestine; insulin regulation; insulin secretion; intestinal villi; lacteal; lymph flow; lymphatic circulation; male; mast cell; novel; nutrient metabolism; prevent; response; sex; sex cycle

Project Summary While the physiological importance of lymph chylomicron transport is well-documented, the physiological roles of other lymph factors remain poorly understood. This is a critical area for additional new research, as indicated in the RFA, which requests that applications determine “how the signals lymphatics are receiving may affect their function and, thus overall intestinal function”. In order to study these relationships, we will use the rat lymph-fistula model, a novel and powerful paradigm that is routine in our lab, to study the secretion of hormones and other GI factors in vivo. Using this paradigm, we initially demonstrated that lymphatic concentrations of incretin hormones (GLP-1, GIP) are markedly higher than those in the portal or systemic circulation. Our new preliminary data indicate the intriguing possibility that the lymph also transports locally-produced glucocorticoid hormones in response to dietary lipids, and that the lymphatic transport of dietary lipids and hormones varies in a sex- and/or estrous cycle-dependent manner. The present proposal addresses the overall hypothesis that the transport and signaling of hormones and related factors within the GI lymphatic system is necessary for normal functioning of the GI tract and for overall metabolic health. Aim 1 determines the physiological relevance of high incretin concentrations in intestinal lymph. We assess the impact of lymph diversion on glucose absorption and distribution, and determine the mechanisms by which the stomach regulates incretin secretion during nutrient ingestion. Aim 2 determines the physiological relevance of nutrient-induced glucocorticoid hormones in intestinal lymph. We identify the source of the lymphatic glucocorticoid response to lipids, and determine the extent that lymphatic glucocorticoids regulate lipid absorption and its associated proinflammatory response. Aim 3 determines the role of sex and the estrous cycle in intestinal lymph physiology. We evaluate the extent that lymphatic transport functions (for chylomicrons, incretins, inflammatory mediators, and glucocorticoids) vary with sex and/or the estrous cycle, and test the mechanistic role of ovarian hormones in these processes. This multi-PI proposal leverages the complementary expertise of a highly collaborative team that includes Dr. Patrick Tso (expert in GI lymphatics and metabolic hormones), Dr. Yvonne Ulrich-Lai (expert in the HPA axis and corticosterone signaling), and Dr. Min Liu (expert in ovarian hormone signaling and energy balance).

项目概要 虽然淋巴乳糜微粒运输的生理重要性已得到充分证明， 其他淋巴因子的生理作用仍知之甚少，这是需要更多新发现的关键领域。 正如 RFA 中所指出的，该研究要求应用程序确定“淋巴管信号如何 接收可能会影响它们的功能，从而影响整体肠道功能”。为了研究这些关系，我们。 将使用大鼠淋巴瘘模型（我们实验室常用的一种新颖而强大的范例）来研究 使用这种范例，我们最初证明了体内激素和其他胃肠道因子的分泌。 肠促胰岛素激素（GLP-1、GIP）的淋巴浓度明显高于门脉或 我们新的初步数据表明，全身淋巴液也有运输这一有趣的可能性。 本地产生的糖皮质激素对饮食脂质做出反应，并且淋巴运输 膳食脂质和激素的变化取决于性别和/或动情周期。 解决了胃肠道内激素及相关因素的运输和信号传导的总体假设 淋巴系统对于胃肠道的正常功能和整体代谢健康至关重要。 确定肠道淋巴中高肠促胰素浓度的生理相关性。 淋巴转移对葡萄糖吸收和分布的影响，并确定其机制 胃在营养摄入过程中调节肠促胰素分泌，目标 2 确定了生理相关性。 肠道淋巴液中营养诱导的糖皮质激素我们确定了淋巴管的来源。 糖皮质激素对脂质的反应，并确定淋巴糖皮质激素调节脂质的程度 吸收及其相关的促炎反应决定了性和动情的作用。 我们评估肠道淋巴生理学的循环程度。 乳糜微粒、肠降血糖素、炎症介质和糖皮质激素）随性别和/或动情周期而变化， 并测试卵巢激素在这些过程中的机制作用。这个多 PI 提案利用了 高度协作团队的互补专业知识，其中包括 Patrick Tso 博士（胃肠道淋巴学专家） 和代谢激素）、Yvonne Ulrich-Lai 博士（HPA 轴和皮质酮信号传导专家）和 刘敏（卵巢激素信号传导和能量平衡专家）。