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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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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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 |
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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 |
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