ArticleScience advances2019
Hepatocyte-specific HIF-1α ablation improves obesity-induced glucose intolerance by reducing first-pass GLP-1 degradation.
Article in Science advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 27 citations in OpenAlex.
- Hepatic HIF2α Modulates Extra-Hepatic Disease-Associated Phenotypes During Metabolic Dysfunction-Associated Steatotic Liver Disease.Comprehensive physiology · 2026Article
- The Multifaceted Nature of GLP-1: Molecular Mechanisms and Signaling Pathways in Metabolic and Neurodegenerative Diseases.International journal of molecular sciences · 2026Review
- Association of HIF1α, BNIP3, and BNIP3L with Hypoxia-Related Metabolic Stress in Metabolic Syndrome.Medicina (Kaunas, Lithuania) · 2026Article
- Immunometabolism in obesity: Understanding the beneficial and detrimental roles of inflammation.PLoS biology · 2026Article
- Puerarin Targets HIF-1α to Modulate Hypoxia-Related Sphingolipid Metabolism in Diabetic Hepatopathy via the SPTLC2/Ceramide Pathway.Pharmaceuticals (Basel, Switzerland) · 2025Article
- The role of hypoxia-inducible factors 1 and 2 in the pathogenesis of diabetic kidney disease.Journal of nephrology · 2025Review
- Nicotinamide Mononucleotide (NMN) Ameliorates Free Fatty Acid-Induced Pancreatic β-Cell Dysfunction via the NADInternational journal of molecular sciences · 2024Article
- HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis.Science translational medicine · 2024Article
- Hypoxia-Induced Signaling in Gut and Liver Pathobiology.Annual review of pathology · 2024Review
- Inter-organ crosstalk during development and progression of type 2 diabetes mellitus.Nature reviews. Endocrinology · 2024Review
- Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets.Signal transduction and targeted therapy · 2023Review
- Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, modulates glucose production, and when absent influences NAFLD progression.JCI insight · 2023Article
- HIF-2α Preserves Mitochondrial Activity and Glucose Sensing in Compensating β-Cells in Obesity.Diabetes · 2022Article
- Article
- Cardiovascular Effects of Incretin-Based Therapies: Integrating Mechanisms With Cardiovascular Outcome Trials.Diabetes · 2022Review
- Elucidating Drug-Like Compounds and Potential Mechanisms of Corn Silk (Current issues in molecular biology · 2021Article
- ANT2 drives proinflammatory macrophage activation in obesity.JCI insight · 2021Article
- The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma.Cancers · 2021Review
- BRG1 Links TLR4 Trans-Activation to LPS-Induced SREBP1a Expression and Liver Injury.Frontiers in cell and developmental biology · 2021Article
- Inhibition of prolyl hydroxylases increases hepatic insulin and decreases glucagon sensitivity by an HIF-2α-dependent mechanism.Molecular metabolism · 2020Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The decrease in incretin effects is an important etiologic component of type 2 diabetes with unknown mechanisms. In an attempt to understand obesity-induced changes in liver oxygen homeostasis, we found that liver HIF-1α expression was increased mainly by soluble factors released from obese adipocytes, leading to decreased incretin effects. Deletion of hepatocyte HIF-1α protected obesity-induced glucose intolerance without changes in body weight, liver steatosis, or insulin resistance. In-depth mouse metabolic phenotyping revealed that obesity increased first-pass degradation of an incretin hormone GLP-1 with increased liver DPP4 expression and decreased sinusoidal blood flow rate, reducing active GLP-1 levels in peripheral circulation. Hepatocyte HIF-1α KO blocked these changes induced by obesity. Deletion of hepatocyte HIF-2α did not change liver DPP4 expression but improved hepatic steatosis. Our results identify a previously unknown pathway for obesity-induced impaired beta cell glucose response (incretin effects) and the development of glucose intolerance through inter-organ communications.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.