Role of Nutrient Sensing Receptors for the Gut Microbiota in Metabolism

摘要 2型糖尿病是我们社会面临的最严重的医学疾病之一， 了解导致T2D的事件，特别是肥胖和胰岛素的起源 电阻是T2D的关键组件，它是至关重要的。纤维，这是已知的保护免受 T2D，由肠道细菌发酵，合成短链脂肪酸(SCFA)， 主要是醋酸盐、丙酸盐和丁酸盐。这是提议的关键机制之一。 肠道微生物群对这些新陈代谢条件具有保护作用。重要的是，游离脂肪酸 感知和介导SCFAs作用的受体2(FFA2)和-3(FFA3)发生了变化 在肥胖和胰岛素抵抗状态下的表达。这些受体在β细胞中表达，并且 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- 调节β细胞功能的类肽-1，它们共同参与分泌 胰岛素。因此，这些受体被用来调节细菌之间的相互作用。 发酵产生单链脂肪酸和激素分泌。我们建议使用新的基因敲除(KO) 小鼠模型解剖纤维(通过SCFA的产生)如何调节代谢结果，如 肥胖和胰岛素抵抗，我们将在全身(全球，目标1)和组织- 具体水平(目标2)，侧重于肠岛轴线，并评估翻译部分 这些受体对人体组织的作用(目标3)。总体而言，这项研究将揭示一个新颖的SCFA- 感知机制影响宿主对肥胖挑战的代谢反应。

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.