Cargando…

Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess, and an increased risk of cardiovascular morbidity. Here we evaluate systemic and...

Descripción completa

Detalles Bibliográficos
Autores principales: Westgate, Connar S.J., Botfield, Hannah F., Alimajstorovic, Zerin, Yiangou, Andreas, Walsh, Mark, Smith, Gabrielle, Singhal, Rishi, Mitchell, James L., Grech, Olivia, Markey, Keira A., Hebenstreit, Daniel, Tennant, Daniel A., Tomlinson, Jeremy W., Mollan, Susan P., Ludwig, Christian, Akerman, Ildem, Lavery, Gareth G., Sinclair, Alexandra J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262372/
https://www.ncbi.nlm.nih.gov/pubmed/33848268
http://dx.doi.org/10.1172/jci.insight.145346
_version_ 1783719179341266944
author Westgate, Connar S.J.
Botfield, Hannah F.
Alimajstorovic, Zerin
Yiangou, Andreas
Walsh, Mark
Smith, Gabrielle
Singhal, Rishi
Mitchell, James L.
Grech, Olivia
Markey, Keira A.
Hebenstreit, Daniel
Tennant, Daniel A.
Tomlinson, Jeremy W.
Mollan, Susan P.
Ludwig, Christian
Akerman, Ildem
Lavery, Gareth G.
Sinclair, Alexandra J.
author_facet Westgate, Connar S.J.
Botfield, Hannah F.
Alimajstorovic, Zerin
Yiangou, Andreas
Walsh, Mark
Smith, Gabrielle
Singhal, Rishi
Mitchell, James L.
Grech, Olivia
Markey, Keira A.
Hebenstreit, Daniel
Tennant, Daniel A.
Tomlinson, Jeremy W.
Mollan, Susan P.
Ludwig, Christian
Akerman, Ildem
Lavery, Gareth G.
Sinclair, Alexandra J.
author_sort Westgate, Connar S.J.
collection PubMed
description BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess, and an increased risk of cardiovascular morbidity. Here we evaluate systemic and adipose specific metabolic determinants of the IIH phenotype. METHODS: In fasted, matched IIH (n = 97) and control (n = 43) patients, we assessed glucose and insulin homeostasis and leptin levels. Body composition was assessed along with an interrogation of adipose tissue function via nuclear magnetic resonance metabolomics and RNA sequencing in paired omental and subcutaneous biopsies in a case-control study. RESULTS: We demonstrate an insulin- and leptin-resistant phenotype in IIH in excess of that driven by obesity. Adiposity in IIH is preferentially centripetal and is associated with increased disease activity and insulin resistance. IIH adipocytes appear transcriptionally and metabolically primed toward depot-specific lipogenesis. CONCLUSION: These data show that IIH is a metabolic disorder in which adipose tissue dysfunction is a feature of the disease. Managing IIH as a metabolic disease could reduce disease morbidity and improve cardiovascular outcomes. FUNDING: This study was supported by the UK NIHR (NIHR-CS-011-028), the UK Medical Research Council (MR/K015184/1), Diabetes UK, Wellcome Trust (104612/Z/14/Z), the Sir Jules Thorn Award, and the Midlands Neuroscience Teaching and Research Fund.
format Online
Article
Text
id pubmed-8262372
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher American Society for Clinical Investigation
record_format MEDLINE/PubMed
spelling pubmed-82623722021-07-13 Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension Westgate, Connar S.J. Botfield, Hannah F. Alimajstorovic, Zerin Yiangou, Andreas Walsh, Mark Smith, Gabrielle Singhal, Rishi Mitchell, James L. Grech, Olivia Markey, Keira A. Hebenstreit, Daniel Tennant, Daniel A. Tomlinson, Jeremy W. Mollan, Susan P. Ludwig, Christian Akerman, Ildem Lavery, Gareth G. Sinclair, Alexandra J. JCI Insight Clinical Medicine BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess, and an increased risk of cardiovascular morbidity. Here we evaluate systemic and adipose specific metabolic determinants of the IIH phenotype. METHODS: In fasted, matched IIH (n = 97) and control (n = 43) patients, we assessed glucose and insulin homeostasis and leptin levels. Body composition was assessed along with an interrogation of adipose tissue function via nuclear magnetic resonance metabolomics and RNA sequencing in paired omental and subcutaneous biopsies in a case-control study. RESULTS: We demonstrate an insulin- and leptin-resistant phenotype in IIH in excess of that driven by obesity. Adiposity in IIH is preferentially centripetal and is associated with increased disease activity and insulin resistance. IIH adipocytes appear transcriptionally and metabolically primed toward depot-specific lipogenesis. CONCLUSION: These data show that IIH is a metabolic disorder in which adipose tissue dysfunction is a feature of the disease. Managing IIH as a metabolic disease could reduce disease morbidity and improve cardiovascular outcomes. FUNDING: This study was supported by the UK NIHR (NIHR-CS-011-028), the UK Medical Research Council (MR/K015184/1), Diabetes UK, Wellcome Trust (104612/Z/14/Z), the Sir Jules Thorn Award, and the Midlands Neuroscience Teaching and Research Fund. American Society for Clinical Investigation 2021-05-24 /pmc/articles/PMC8262372/ /pubmed/33848268 http://dx.doi.org/10.1172/jci.insight.145346 Text en © 2021 Westgate et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Clinical Medicine
Westgate, Connar S.J.
Botfield, Hannah F.
Alimajstorovic, Zerin
Yiangou, Andreas
Walsh, Mark
Smith, Gabrielle
Singhal, Rishi
Mitchell, James L.
Grech, Olivia
Markey, Keira A.
Hebenstreit, Daniel
Tennant, Daniel A.
Tomlinson, Jeremy W.
Mollan, Susan P.
Ludwig, Christian
Akerman, Ildem
Lavery, Gareth G.
Sinclair, Alexandra J.
Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension
title Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension
title_full Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension
title_fullStr Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension
title_full_unstemmed Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension
title_short Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension
title_sort systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension
topic Clinical Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262372/
https://www.ncbi.nlm.nih.gov/pubmed/33848268
http://dx.doi.org/10.1172/jci.insight.145346
work_keys_str_mv AT westgateconnarsj systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT botfieldhannahf systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT alimajstoroviczerin systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT yiangouandreas systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT walshmark systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT smithgabrielle systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT singhalrishi systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT mitchelljamesl systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT grecholivia systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT markeykeiraa systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT hebenstreitdaniel systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT tennantdaniela systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT tomlinsonjeremyw systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT mollansusanp systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT ludwigchristian systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT akermanildem systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT laverygarethg systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension
AT sinclairalexandraj systemicandadipocytetranscriptionalandmetabolicdysregulationinidiopathicintracranialhypertension