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

在2型糖尿病患者中，基于胰高血糖素样肽（GLP）1的治疗显著降低了 无低血糖风险的高血糖。然而，这些药物的不良肠道事件 治疗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GLP 1不引起这样的肠道事件并产生上级代谢作用。 尽管有这样的证据，由于GLP 1促分泌素的缺口， 了解GLP 1分泌机制。我们的初步数据显示肠道缺氧- 诱导因子（HIF）信号增强小鼠GLP 1分泌并改善血糖 以GLP 1依赖的方式耐受。我们发现肠道HIF，特别是HIF-2α， 通过诱导脂质传感器的表达增强脂肪酸刺激的GLP 1分泌 G蛋白偶联受体（GPR）40，在肠道L细胞中富集。考虑到营养物质调节 GLP 1分泌，我们的研究调查了肠道HIF-2α信号传导是否与饮食线索有关 与GLP 1分泌通过营养感应机制，并阐明其代谢的影响。 作为支持，我们发现小鼠肠道HIF-2α的破坏降低了GPR 40的表达， 降低GLP 1水平。此外，在禁食期间急性抑制HIF-2α可减弱GPR 40， 表达和废除脂质刺激的GLP 1分泌，证明了新的作用， 肠HIF-2α在餐后GLP-1分泌中的作用我们发现TCA代谢物的流量改变 α-酮戊二酸（α-KG）与上皮细胞中HIF-2α信号的诱导有关。 因此，目的1将阐明上皮代谢流是否动态调节L-细胞HIF-2α 信号Aim 2将明确HIF-2α调控GLP 1的分子机制 分泌物我们的数据表明，肠道HIF-2α的激活减弱了饮食诱导的葡萄糖 不耐受和肝脂肪变性，与GLP 1水平升高相关。鉴于这一提高 餐后GLP 1可改善葡萄糖不耐受，目标3将测试我们的假设，即L细胞 HIF 2 α可通过升高GLP 1水平，防止饮食诱导的代谢紊乱， L细胞中HIF-2α增加或缺失的小鼠。最后，我们将确定是否激活HIF-2α， 将使用人类肠道类器官系统在人类中诱导GLP 1。考虑到这种强有力的HIF- 有2种诱导剂可用于了解肠HIF-2α在营养感测中的作用， 代谢稳态可能导致新的策略，以诱导内源性GLP 1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.