Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension

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Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension. / Westgate, Connar; Botfield, Hannah; Alimajstorovic, Zerin; Yiangou, Andreas; Walsh, Mark; Smith, Gabrielle; Singhal, Rishi; Mitchell, James; Grech, Olivia; Markey, Keira; Hebenstreit, Daniel; Tennant, Daniel; Tomlinson, Jeremy; Mollan, Susan; Ludwig, Christian; Akerman, Ildem; Lavery, Gareth; Sinclair, Alex.

In: JCI Insight, Vol. 6, No. 10, e145346, 24.05.2021.

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@article{b93225a5d87c43fb8bd69634a858542e,
title = "Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension",
abstract = "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.",
author = "Connar Westgate and Hannah Botfield and Zerin Alimajstorovic and Andreas Yiangou and Mark Walsh and Gabrielle Smith and Rishi Singhal and James Mitchell and Olivia Grech and Keira Markey and Daniel Hebenstreit and Daniel Tennant and Jeremy Tomlinson and Susan Mollan and Christian Ludwig and Ildem Akerman and Gareth Lavery and Alex Sinclair",
note = "Funding Information: 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. Funding Information: We wish to thank Nicola Crabtree of University Hospitals Birmingham for performing and analyzing the DEXA scans. This study was funded by the UK NIHR Clinician Scientist Fellowship (NIHR-CS-011-028) and the UK Medical Research Council UK (project grant MR/K015184/1 to AJS and a Midlands Neuroscience Teaching and Research Fund grant awarded to CSJW. AJS was awarded a Sir Jules Thorn Award for Biomedical Research. GGL was supported by a Wellcome Trust Senior Research Fellowship (104612/Z/14/Z). IA was funded by RD Lawrence Fellowship (Diabetes UK). The views expressed are those of the authors and not necessarily those of the UK NHS, the UK NIHR, or the UK Department of Health and Social Care. Publisher Copyright: Copyright: {\textcopyright} 2021, Westgate et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2021",
month = may,
day = "24",
doi = "10.1172/jci.insight.145346",
language = "English",
volume = "6",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "American Society for Clinical Investigation",
number = "10",

}

RIS

TY - JOUR

T1 - Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension

AU - Westgate, Connar

AU - Botfield, Hannah

AU - Alimajstorovic, Zerin

AU - Yiangou, Andreas

AU - Walsh, Mark

AU - Smith, Gabrielle

AU - Singhal, Rishi

AU - Mitchell, James

AU - Grech, Olivia

AU - Markey, Keira

AU - Hebenstreit, Daniel

AU - Tennant, Daniel

AU - Tomlinson, Jeremy

AU - Mollan, Susan

AU - Ludwig, Christian

AU - Akerman, Ildem

AU - Lavery, Gareth

AU - Sinclair, Alex

N1 - Funding Information: 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. Funding Information: We wish to thank Nicola Crabtree of University Hospitals Birmingham for performing and analyzing the DEXA scans. This study was funded by the UK NIHR Clinician Scientist Fellowship (NIHR-CS-011-028) and the UK Medical Research Council UK (project grant MR/K015184/1 to AJS and a Midlands Neuroscience Teaching and Research Fund grant awarded to CSJW. AJS was awarded a Sir Jules Thorn Award for Biomedical Research. GGL was supported by a Wellcome Trust Senior Research Fellowship (104612/Z/14/Z). IA was funded by RD Lawrence Fellowship (Diabetes UK). The views expressed are those of the authors and not necessarily those of the UK NHS, the UK NIHR, or the UK Department of Health and Social Care. Publisher Copyright: Copyright: © 2021, Westgate et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

PY - 2021/5/24

Y1 - 2021/5/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85106459925&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.145346

DO - 10.1172/jci.insight.145346

M3 - Article

C2 - 33848268

VL - 6

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 10

M1 - e145346

ER -