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

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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.