Role of Nutrient Sensing Receptors for the Gut Microbiota in Metabolism

摘要 2型糖尿病（T2 D）是我们社会面临的最严重的医学疾病之一， 了解导致T2 D的事件，特别是肥胖和胰岛素的起源 作为T2 D的关键组成部分，耐药性至关重要。纤维，这是已知的保护， T2 D由肠道细菌发酵，导致短链脂肪酸（SCFA）的合成， 主要是乙酸盐、丙酸盐和丁酸盐。这是提议的关键机制之一 肠道微生物组可以保护这些代谢条件。重要的是，游离脂肪酸 感受和介导SCFA作用的受体2（FFA 2）和受体3（FFA 3）已经改变， 在肥胖和胰岛素抵抗状态中的表达。这些受体在β细胞中表达， 在肠内分泌（L）细胞中，它们被认为有助于胰高血糖素的分泌- 如肽-1（GLP-1）调节β细胞功能，共同促进分泌 胰岛素因此，这些受体介导了细菌与细菌之间的相互作用。 发酵到SCFAs和激素分泌。我们建议使用新的基因敲除（KO） 小鼠模型来剖析纤维（通过SCFA产生）如何介导代谢结果， 肥胖和胰岛素抵抗，我们将在全身（全球，目标1）和组织中进行探索- 特定水平（目标2），侧重于肠岛轴，并评估平移分量 这些受体的人体组织（目的3）。总的来说，这项研究将揭示一种新的SCFA- 感受机制影响宿主对致肥胖攻击的代谢反应。

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.