Role of Hypoxia-inducible factor-2a in L-cell nutrient sensing and metabolic homeostasis

在2型糖尿病患者中，以胰高血糖素样肽(GLP)1为基础的治疗大大降低 无低血糖风险的高血糖。然而，与这些相关的不良肠道事件 治疗方法限制了剂量的增加，并降低了患者的依从性。研究表明， 内源性GLP1不会引起这样的肠道事件，并产生更好的代谢效应。 尽管有这样的证据，但由于细胞间隙，目前还没有针对L细胞的Glp1促分泌剂。 了解GLP1的分泌机制。我们的初步数据显示，肠道缺氧- 诱导因子(HIF)信号转导促进小鼠GLP1分泌并改善血糖 以依赖于GLP1的方式耐受。我们发现，肠道缺氧诱导因子，尤其是缺氧诱导因子-2α， 通过诱导脂质感受器的表达来增强脂肪酸刺激的GLP1的分泌 G蛋白偶联受体(GPR)40，丰富于肠道L细胞。鉴于营养物质调节 GLP1的分泌，我们的研究调查了肠道HIF-2α信号是否与饮食线索有关 通过营养感应机制与GLP1的分泌有关，并阐明其代谢意义。 在支持方面，我们发现破坏小鼠肠道缺氧诱导因子-2α降低了GPR40的表达，并 降低GLP1水平。此外，在禁食期间急性抑制缺氧诱导因子-2α可减弱GPR40 表达并取消脂刺激的GLP1分泌，展示了一种新的作用 肠内缺氧诱导因子-2α的餐后分泌。我们发现了一种不同流量的TCA代谢物 α-酮戊二酸(α-KG)与诱导上皮细胞HIF-2α信号转导有关。 因此，目标1将阐明上皮代谢流是否动态调节L细胞的HIF-2α 发信号。Aim 2将确定HIF-2α调节Glp1的分子机制 分泌物。我们的数据显示，肠道缺氧诱导因子-2α的激活可以降低饮食诱导的血糖 不耐受和肝脏脂肪变性，与GLP1水平升高相关。考虑到这一点 餐后Glp1改善糖耐量异常，Aim 3将测试我们的假设，即L细胞 HIF2α将通过提高GLP1水平来保护饮食诱导的代谢紊乱 缺氧诱导因子-2α在L细胞中的表达增减。最后，我们将确定是否激活HIF-2α 将使用人体肠道器官系统在人类体内诱导GLP1。考虑到强大的HIF- 2诱导剂可用于了解肠道缺氧诱导因子-2α在营养感知和 代谢稳态可能导致新的策略来诱导内源性GLP1的分泌 代谢性疾病。

In type 2 diabetic patients, glucagon-like peptide (GLP)1-based therapies profoundly lower hyperglycemia without hypoglycemic risk. However, adverse intestinal events with these therapies limit dose escalations and decrease patient compliance. Studies show that endogenous GLP1 do not cause such intestinal events and yield superior metabolic effects. Despite such evidence, no GLP1 secretagogue targeting L-cells is available due to a gap in understanding GLP1 secretory mechanisms. Our preliminary data show that intestinal hypoxia- inducible factor (HIF) signaling enhances GLP1 secretion in mice and improves glucose tolerance in a GLP1-dependent manner. We found that intestinal HIF, particularly HIF-2α, potentiates fatty acid-stimulated GLP1 secretion by inducing the expression of the lipid sensor G-protein coupled receptor (GPR) 40, enriched in intestinal L-cells. Given that nutrients regulate GLP1 secretion, our study investigates whether intestinal HIF-2α signaling links dietary cues with GLP1 secretion via a nutrient-sensing mechanism and elucidates its metabolic implications. In support, we show that disruption of intestinal HIF-2α in mice reduces GPR40 expression and decreases GLP1 levels. Moreover, acute inhibition of HIF-2α during fasting attenuates GPR40 expression and abolishes lipid-stimulated GLP1 secretion, demonstrating a novel role of intestinal HIF-2α in postprandial GLP1 secretion. We identified an altered flux of TCA metabolite α-ketoglutarate (α-KG) is associated with the induction of HIF-2α signaling in epithelial cells. Thus, Aim 1 will elucidate whether epithelial metabolic flux dynamically regulates L-cell HIF-2α signaling. And Aim 2 will determine the molecular mechanism by which HIF-2α regulates GLP1 secretion. Our data show that activation of intestinal HIF-2α attenuates diet-induced glucose intolerance and hepatic steatosis, associated with elevated GLP1 levels. Given that elevated postprandial GLP1 ameliorates glucose intolerance, Aim 3 will test our postulation that L-cell HIF2α will protect against diet-induced metabolic perturbations by elevating GLP1 levels using mice with gain or loss of HIF-2α in L-cells. Lastly, we will establish whether activating HIF-2α will induce GLP1 in humans using the human intestinal organoid system. Given that potent HIF- 2 inducers are available understanding the role of intestinal HIF-2α in nutrient sensing and metabolic homeostasis may lead to novel strategies to induce endogenous GLP1 secretion in metabolic diseases.