title: A liver Hif-2α-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition.
abstract: Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein. Further, liver Irs2 was both necessary and sufficient to mediate Hif-2α and Vegf inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between Hif-2α-mediated hypoxic signaling and hepatic insulin action through Irs2 induction, which can be co-opted by Vegf inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for Hif-1α, which promotes glycolysis, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.
authors.affiliation: Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wei
authors.affiliation: Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Piecewicz
authors.affiliation: Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: McGinnis
authors.affiliation: Division of Radiation Oncology Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Cullen M
authors.initials: CM
authors.lastname: Taniguchi
authors.affiliation: Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York, 10591, USA.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Wiegand
authors.affiliation: Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York, 10591, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Carol W-M
authors.initials: CW
authors.lastname: Chan
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville TN 37232, USA.
authors.forename: Kimberly X
authors.initials: KX
authors.lastname: Mulligan
authors.affiliation: Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kuo
authors.affiliation: Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Vallon
authors.affiliation: Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York, 10591, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Morton
authors.affiliation: INSERM U 1060, INRA 1235, Universite de Lyon, Faculté de Médecine Lyon Sud - BP12, 69921 OULLINS Cedex, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.affiliation: Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.affiliation: UCSF Liver Center, San Francisco General Hospital, 1001 Potrero Ave. Building 40, Room 4102, San Francisco, CA 94110.
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Maher
authors.affiliation: Inserm U855/Université Lyon, Faculté Lyon Est Laennec, 7 rue Guillaume Paradin, 69372 Lyon cedex 08, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Mithieux
authors.affiliation: Inserm U855/Université Lyon, Faculté Lyon Est Laennec, 7 rue Guillaume Paradin, 69372 Lyon cedex 08, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rajas
authors.affiliation: Division of Endocrinology and Metabolism, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Annes
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville TN 37232, USA.
authors.forename: Owen P
authors.initials: OP
authors.lastname: McGuinness
authors.affiliation: Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York, 10591, USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.affiliation: Division of Radiation Oncology Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.affiliation: Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C526298:Irs2 protein, mouse
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