A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition

Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis(1,2). The liver possesses a rich sinusoidal capillary network with increased hypoxia and decreased gluconeogenesis in the perivenous zone(3). Here, diverse v...

Descripción completa

Detalles Bibliográficos
Autores principales: Wei, Kevin, Piecewicz, Stephanie M., McGinnis, Lisa M., Taniguchi, Cullen M., Wiegand, Stanley J., Anderson, Keith, Chan, Carol W-M., Mulligan, Kimberly X., Kuo, David, Yuan, Jenny, Vallon, Mario, Morton, Lori, Lefai, Etienne, Simon, M. Celeste, Maher, Jacquelyn J., Mithieux, Gilles, Rajas, Fabienne, Annes, Justin, McGuinness, Owen P., Thurston, Gavin, Giaccia, Amato J., Kuo, Calvin J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795838/
https://www.ncbi.nlm.nih.gov/pubmed/24037094
http://dx.doi.org/10.1038/nm.3295
_version_ 1782287434916036608
author Wei, Kevin
Piecewicz, Stephanie M.
McGinnis, Lisa M.
Taniguchi, Cullen M.
Wiegand, Stanley J.
Anderson, Keith
Chan, Carol W-M.
Mulligan, Kimberly X.
Kuo, David
Yuan, Jenny
Vallon, Mario
Morton, Lori
Lefai, Etienne
Simon, M. Celeste
Maher, Jacquelyn J.
Mithieux, Gilles
Rajas, Fabienne
Annes, Justin
McGuinness, Owen P.
Thurston, Gavin
Giaccia, Amato J.
Kuo, Calvin J.
author_facet Wei, Kevin
Piecewicz, Stephanie M.
McGinnis, Lisa M.
Taniguchi, Cullen M.
Wiegand, Stanley J.
Anderson, Keith
Chan, Carol W-M.
Mulligan, Kimberly X.
Kuo, David
Yuan, Jenny
Vallon, Mario
Morton, Lori
Lefai, Etienne
Simon, M. Celeste
Maher, Jacquelyn J.
Mithieux, Gilles
Rajas, Fabienne
Annes, Justin
McGuinness, Owen P.
Thurston, Gavin
Giaccia, Amato J.
Kuo, Calvin J.
author_sort Wei, Kevin
collection PubMed
description Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis(1,2). The liver possesses a rich sinusoidal capillary network with increased hypoxia and decreased gluconeogenesis in the perivenous zone(3). Here, diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in normal or diabetic db/db mice, potentiating hepatic insulin signaling, decreasing gluconeogenic gene expression, increasing glycogen storage and suppressing hepatic glucose production (HGP). VEGF inhibition induced hepatic hypoxia via sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia inducible factor-2α (HIF-2α) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling via direct and indirect induction of insulin receptor substrate 2 (IRS2), an essential insulin receptor adaptor protein(4–6). 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 via 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(7–9), versus HIF-2α, which suppresses gluconeogenesis, and suggest novel treatment approaches for type 2 diabetes mellitus.
format Online
Article
Text
id pubmed-3795838
institution National Center for Biotechnology Information
language English
publishDate 2013
record_format MEDLINE/PubMed
spelling pubmed-37958382014-04-01 A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition Wei, Kevin Piecewicz, Stephanie M. McGinnis, Lisa M. Taniguchi, Cullen M. Wiegand, Stanley J. Anderson, Keith Chan, Carol W-M. Mulligan, Kimberly X. Kuo, David Yuan, Jenny Vallon, Mario Morton, Lori Lefai, Etienne Simon, M. Celeste Maher, Jacquelyn J. Mithieux, Gilles Rajas, Fabienne Annes, Justin McGuinness, Owen P. Thurston, Gavin Giaccia, Amato J. Kuo, Calvin J. Nat Med Article Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis(1,2). The liver possesses a rich sinusoidal capillary network with increased hypoxia and decreased gluconeogenesis in the perivenous zone(3). Here, diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in normal or diabetic db/db mice, potentiating hepatic insulin signaling, decreasing gluconeogenic gene expression, increasing glycogen storage and suppressing hepatic glucose production (HGP). VEGF inhibition induced hepatic hypoxia via sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia inducible factor-2α (HIF-2α) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling via direct and indirect induction of insulin receptor substrate 2 (IRS2), an essential insulin receptor adaptor protein(4–6). 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 via 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(7–9), versus HIF-2α, which suppresses gluconeogenesis, and suggest novel treatment approaches for type 2 diabetes mellitus. 2013-09-15 2013-10 /pmc/articles/PMC3795838/ /pubmed/24037094 http://dx.doi.org/10.1038/nm.3295 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wei, Kevin
Piecewicz, Stephanie M.
McGinnis, Lisa M.
Taniguchi, Cullen M.
Wiegand, Stanley J.
Anderson, Keith
Chan, Carol W-M.
Mulligan, Kimberly X.
Kuo, David
Yuan, Jenny
Vallon, Mario
Morton, Lori
Lefai, Etienne
Simon, M. Celeste
Maher, Jacquelyn J.
Mithieux, Gilles
Rajas, Fabienne
Annes, Justin
McGuinness, Owen P.
Thurston, Gavin
Giaccia, Amato J.
Kuo, Calvin J.
A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition
title A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition
title_full A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition
title_fullStr A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition
title_full_unstemmed A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition
title_short A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition
title_sort liver hif-2α/irs2 pathway sensitizes hepatic insulin signaling and is modulated by vegf inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795838/
https://www.ncbi.nlm.nih.gov/pubmed/24037094
http://dx.doi.org/10.1038/nm.3295
work_keys_str_mv AT weikevin aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT piecewiczstephaniem aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mcginnislisam aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT taniguchicullenm aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT wiegandstanleyj aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT andersonkeith aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT chancarolwm aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mulligankimberlyx aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT kuodavid aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT yuanjenny aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT vallonmario aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mortonlori aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT lefaietienne aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT simonmceleste aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT maherjacquelynj aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mithieuxgilles aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT rajasfabienne aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT annesjustin aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mcguinnessowenp aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT thurstongavin aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT giacciaamatoj aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT kuocalvinj aliverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT weikevin liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT piecewiczstephaniem liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mcginnislisam liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT taniguchicullenm liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT wiegandstanleyj liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT andersonkeith liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT chancarolwm liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mulligankimberlyx liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT kuodavid liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT yuanjenny liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT vallonmario liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mortonlori liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT lefaietienne liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT simonmceleste liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT maherjacquelynj liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mithieuxgilles liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT rajasfabienne liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT annesjustin liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT mcguinnessowenp liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT thurstongavin liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT giacciaamatoj liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition
AT kuocalvinj liverhif2airs2pathwaysensitizeshepaticinsulinsignalingandismodulatedbyvegfinhibition