title: HIF2α Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling.
abstract: Glucagon drives hepatic gluconeogenesis and maintains blood glucose levels during fasting. The mechanism that attenuates glucagon action following refeeding is not understood. The present study demonstrates an increase in perivenous liver hypoxia immediately after feeding, which stabilizes hypoxia-inducible factor 2α (HIF2α) in liver. The transient postprandial increase in hepatic HIF2α attenuates glucagon signaling. Hepatocyte-specific disruption of HIF2α increases postprandial blood glucose and potentiates the glucagon response. Independent of insulin/AKT signaling, activation of hepatic HIF2α resulted in lower blood glucose, improved glucose tolerance, and decreased gluconeogenesis due to blunted hepatic glucagon action. Mechanistically, HIF2α abrogated glucagon-PKA signaling by activating cAMP-phosphodiesterases in a MEK/ERK-dependent manner. Repression of glucagon signaling by HIF2α ameliorated hyperglycemia in streptozotocin-induced diabetes and acute insulin-resistant animal models. This study reveals that HIF2α is essential for the acute postprandial regulation of hepatic glucagon signaling and suggests HIF2α as a potential therapeutic target in the treatment of diabetes.
authors: Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Sadeesh K
authors: SK
authors: Ramakrishnan
authors: Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Huabing
authors: H
authors: Zhang
authors: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Shogo
authors: S
authors: Takahashi
authors: Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Brook
authors: B
authors: Centofanti
authors: Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Sarvesh
authors: S
authors: Periyasamy
authors: Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Kevin
authors: K
authors: Weisz
authors: Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Zheng
authors: Z
authors: Chen
authors: Department of Biological Chemistry, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Michael D
authors: MD
authors: Uhler
authors: Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Liangyou
authors: L
authors: Rui
authors: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Frank J
authors: FJ
authors: Gonzalez
authors: Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: shahy@umich.edu.
authors: Yatrik M
authors: YM
authors: Shah
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D001786:Blood Glucose; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism*; D005943:Gluconeogenesis; D022781:Hepatocytes / Q000378:metabolism; D006943:Hyperglycemia; D007328:Insulin / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019518:Postprandial Period; D061251:Primary Cell Culture; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D017868:Cyclic AMP-Dependent Protein Kinases; D005934:Glucagon; D007328:Insulin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C494469:VHL protein, mouse
keywords: CREB; ERK; HIF2α; PKA; VHL; glucagon; hypoxia