Role of Nutrient Sensing Receptors for the Gut Microbiota in Metabolism

肠道菌群营养感应受体在代谢中的作用

• 批准号: 10364023
• 负责人: Brian Thomas Layden
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364023
• 关键词: Acetates; Affect; Agonist; B-Lymphocytes; Beta Cell; Biological Assay; Blood; Butyrates; Cell physiology; Cell secretion; Cells; Conflict (Psychology); Data; Development; Diabetes Mellitus; Diet; Dietary Fiber; Dietary Intervention; Disease; Drug Targeting; Event; FFAR2 gene; Fermentation; Fiber; Genetic; Health; Hormone secretion; Human; In Vitro; Individual; Insulin Resistance; Intake; Intervention; Intestines; Knock-out; Knockout Mice; L Cells; Measures; Mediating; Medical; Metabolic; Metabolic Diseases; Metabolism; Modeling; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Outcome; Output; Pathway interactions; Peptide YY; Pharmaceutical Preparations; Pharmacology; Physiology; Production; Propionates; Receptor Signaling; Role; Signal Transduction; Site; Societies; Structure; Structure of beta Cell of islet; Sum; Supplementation; Testing; Therapeutic; Tissues; Translating; Veterans; Volatile Fatty Acids; antagonist; body sense; cell type; detection of nutrient; dietary; glucagon-like peptide 1; gut bacteria; gut microbiome; gut microbiota; human disease; human tissue; insight; insulin secretion; islet; meetings; military veteran; mortality; mouse model; novel; obesogenic; receptor; receptor function; response; therapeutic target; translational potential; translational study; western diet

ABSTRACT Type 2 diabetes (T2D) is one of the most serious medical diseases facing our society, and understanding the events leading to T2D, specifically the genesis of obesity and insulin resistance, key components of T2D, is critical. Fiber, which is known to be protective against T2D, is fermented by gut bacteria, resulting in the synthesis of short chain fatty acids (SCFAs), predominantly acetate, propionate, and butyrate. This is one of the key proposed mechanisms that the gut microbiome protects against these metabolic conditions. Importantly, free fatty acid receptors 2 (FFA2) and -3 (FFA3), which sense and mediate the action of SCFAs, have altered expression in obesity and insulin resistant states. These receptors are expressed in β cells and in enteroendocrine (L) cells, where they are suggested to contribute to the secretion of glucagon- like peptide-1 (GLP-1) regulating β cell function, which collectively contribute to the secretion of insulin. These receptors, therefore, are primed to mediate the interaction between bacterial fermentation to SCFAs and hormonal secretion. We propose to use novel genetic knockout (KO) murine models to dissect how fiber (via SCFA production) mediates metabolic outcomes such as obesity and insulin resistance where we will explore at the whole body (global, Aim 1) and tissue- specific level (Aim 2), focused on the enteroinsular axis, and assess the translational component of these receptors to human tissues (Aim 3). Overall, this study will reveal that a novel SCFA- sensing mechanism influences host metabolic response to obesogenic challenge.

抽象的 2型糖尿病（T2D）是我们社会面临的最严重的医疗疾病之一， 了解导致T2D的事件，特别是肥胖和胰岛素的起源 阻力是T2D的关键组成部分，至关重要。纤维，已知会受到保护 T2D通过肠道细菌发酵，导致短链脂肪酸（SCFA）， 主要是乙酸盐，丙酸和丁酸酯。这是提出的关键机制之一 肠道微生物组可以防止这些代谢条件。重要的是，游离脂肪酸 接收器2（FFA2）和-3（FFA3），感知和介导SCFA的作用，已改变 肥胖和胰岛素耐药态的表达。这些受体在β细胞和 在肠内分泌（L）细胞中，建议它们有助于谷歌的分泌 像Pepper-1（GLP-1）调节性β细胞功能，共同有助于分泌 胰岛素。因此，这些受体被启动以介导细菌之间的相互作用 向SCFAS和HORSEAL分泌发酵。我们建议使用新型的遗传基因敲除（KO） 鼠模型以剖析纤维（通过SCFA生产）如何介导新陈代谢结果，例如 肥胖和胰岛素抵抗，我们将在整个身体探索（全球，目标1）和组织 - 特定水平（AIM 2），专注于肠轴轴，并评估翻译成分 这些受体到人体组织（AIM 3）。总体而言，这项研究将表明一种新颖的SCFA- 感应机制影响宿主对肥胖挑战的代谢反应。