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Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension
Connar S.J. Westgate, … , Gareth G. Lavery, Alexandra J. Sinclair
Connar S.J. Westgate, … , Gareth G. Lavery, Alexandra J. Sinclair
Published April 13, 2021
Citation Information: JCI Insight. 2021;6(10):e145346. https://doi.org/10.1172/jci.insight.145346.
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Clinical Medicine Neuroscience Ophthalmology

Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension

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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.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.

Authors

Connar S.J. Westgate, Hannah F. Botfield, Zerin Alimajstorovic, Andreas Yiangou, Mark Walsh, Gabrielle Smith, Rishi Singhal, James L. Mitchell, Olivia Grech, Keira A. Markey, Daniel Hebenstreit, Daniel A. Tennant, Jeremy W. Tomlinson, Susan P. Mollan, Christian Ludwig, Ildem Akerman, Gareth G. Lavery, Alexandra J. Sinclair

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Figure 6

IIH SC adipose tissue displays a distinct transcriptome.

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IIH SC adipose tissue displays a distinct transcriptome.
Differential ge...
Differential gene expression analysis of SC adipose tissue from control versus IIH patients. (A) Bar plot displaying the number of differentially expressed RefSeq genes at P < 0.05. (B) Gene ontology for significantly downregulated genes in IIH adipose. Gene set enrichment analysis of (C) Ribosomal Subunits, (D) Lipid Biosynthesis, (E) Caloric Intake Up, and (F) Caloric Intake Down against differential expression data from adipose tissue of control versus IIH patients. The green line represents the accumulation of genes in the indicated gene list against the expression pattern in control versus IIH patients (blue, downregulated in samples from IIH; red, upregulated in samples from IIH patients). Control n = 7, IIH n = 13. NES, normalized enrichment score; FDR, false discovery rate.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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