ArticleCellular and molecular gastroenterology and hepatology2022
Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells.
Article in Cellular and molecular gastroenterology and hepatology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 12 citations in OpenAlex.
- Lipid sensing and brain hormone receptors in food intake and glucose regulation.Nature reviews. Endocrinology · 2026Review
- Hypoxia-inducible factor-1 (HIF-1) in the molecular mechanisms of liver fibrosis: research progress on its role and therapeutic strategies.Journal of applied genetics · 2026Review
- The role of hypoxia-inducible factors 1 and 2 in the pathogenesis of diabetic kidney disease.Journal of nephrology · 2025Review
- Effect of hypoxia on GLP-1 secretion - an in vitro study using enteroendocrine STC-1 -cells as a model.Pflugers Archiv : European journal of physiology · 2024Article
- The key role of altered tubule cell lipid metabolism in kidney disease development.Kidney international · 2024Review
- Hypoxia-Induced Signaling in Gut and Liver Pathobiology.Annual review of pathology · 2024Review
- Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets.Signal transduction and targeted therapy · 2023Review
- Iron and the Pathophysiology of Diabetes.Annual review of physiology · 2023Review
- Updated perspective of EPAS1 and the role in pulmonary hypertension.Frontiers in cell and developmental biology · 2023Review
- Hypoxia Hits Glucose Metabolism in the Guts.Cellular and molecular gastroenterology and hepatology · 2022Article
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9 authors at 3 institutions in 1 country.
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Abstract
BACKGROUND &
aimsCompelling evidence shows that glucagon-like peptide-1 (GLP-1) has a profound effect in restoring normoglycemia in type 2 diabetic patients by increasing pancreatic insulin secretion. Although L-cells are the primary source of circulating GLP-1, the current therapies do not target L-cells to increase GLP-1 levels. Our study aimed to determine the molecular underpinnings of GLP-1 secretion as an impetus to identify new interventions to target endogenous L-cells.
methodsWe used genetic mouse models of intestine-specific overexpression of hypoxia-inducible factor (HIF)-1α and HIF-2α (Vhl
resultsOur data show that intestinal HIF signaling improved glucose homeostasis in a GLP-1-dependent manner. Intestinal HIF potentiated GLP-1 secretion via the lipid sensor G-protein-coupled receptor (GPR)40 enriched in L-cells. We show that HIF-2α regulates GPR40 in L-cells and potentiates fatty acid-induced GLP-1 secretion via extracellular regulated kinase (ERK). Using a genetic model of intestine-specific overexpression of HIF-2α, we show that HIF-2α is sufficient to increase GLP-1 levels and attenuate diet-induced metabolic perturbations such as visceral adiposity, glucose intolerance, and hepatic steatosis. Lastly, we show that intestinal HIF-2α signaling acts as a priming mechanism crucial for postprandial lipid-mediated GLP-1 secretion. Thus, disruption of intestinal HIF-2α decreases GLP-1 secretion.
conclusionsIn summary, we show that intestinal HIF signaling, particularly HIF-2α, regulates the lipid sensor GPR40, which is crucial for the lipid-mediated GLP-1 secretion, and suggest that HIF-2α is a potential target to induce endogenous GLP-1 secretion.
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