Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension

Connar Westgate, Hannah Botfield, Zerin Alimajstorovic, Andreas Yiangou, Mark Walsh, Gabrielle Smith, Rishi Singhal, James Mitchell, Olivia Grech, Keira Markey, Daniel Hebenstreit, Daniel Tennant, Jeremy Tomlinson, Susan Mollan, Christian Ludwig, Ildem Akerman, Gareth Lavery, Alex Sinclair

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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.

Original languageEnglish
Article numbere145346
JournalJCI Insight
Issue number10
Early online date13 Apr 2021
Publication statusPublished - 24 May 2021

Bibliographical 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: © 2021, Westgate et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.


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