Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension

BACKGROUNDIdiopathic 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 ad...

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Vydáno v:	JCI insight Ročník 6; číslo 10
Hlavní autoři:	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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Clinical Investigation 24.05.2021 American Society for Clinical investigation
Témata:	Adipocytes Adipocytes - metabolism Adipose tissue Adipose Tissue - metabolism Adult Androgens Biopsy Blood Glucose - metabolism Body composition Body fat Body mass index Cardiovascular diseases Case-Control Studies Clinical Medicine Diabetes Diabetes mellitus Disease Disease resistance Female Genotype & phenotype Glucose Homeostasis Humans Hypertension Insulin - metabolism Insulin resistance Leptin Leptin - metabolism Lipogenesis Mann-Whitney U test Medical research Metabolic Diseases - metabolism Metabolic Diseases - physiopathology Metabolic disorders Metabolism Metabolomics Middle Aged Morbidity Neuroscience NMR Nuclear magnetic resonance Obesity Obesity - metabolism Obesity - physiopathology Ophthalmology Patients Phenotypes Pseudotumor Cerebri - metabolism Pseudotumor Cerebri - physiopathology Triglycerides Weight control Young Adult United Kingdom > UK Obesity Neuroscience Ophthalmology Neurological disorders
ISSN:	2379-3708, 2379-3708
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Abstract	BACKGROUNDIdiopathic 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.METHODSIn 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.RESULTSWe 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.CONCLUSIONThese 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.FUNDINGThis 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.
AbstractList	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. BACKGROUNDIdiopathic 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.METHODSIn 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.RESULTSWe 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.CONCLUSIONThese 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.FUNDINGThis 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.BACKGROUNDIdiopathic 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.METHODSIn 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.RESULTSWe 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.CONCLUSIONThese 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.FUNDINGThis 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. BACKGROUNDIdiopathic 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.METHODSIn 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.RESULTSWe 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.CONCLUSIONThese 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.FUNDINGThis 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.
Author	Tennant, Daniel A. Tomlinson, Jeremy W. Singhal, Rishi Lavery, Gareth G. Botfield, Hannah F. Mitchell, James L. Akerman, Ildem Sinclair, Alexandra J. Smith, Gabrielle Alimajstorovic, Zerin Walsh, Mark Ludwig, Christian Westgate, Connar S.J. Markey, Keira A. Grech, Olivia Hebenstreit, Daniel Mollan, Susan P. Yiangou, Andreas
AuthorAffiliation	3 Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom 2 Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, United Kingdom 1 Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom 4 Department of Neurology, University Hospitals Birmingham National Health Service (NHS) Foundation Trust, Queen Elizabeth Hospital, Birmingham, United Kingdom 6 Upper GI Unit and Minimally Invasive Unit, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham United Kingdom 7 Oxford Centre for Diabetes, Endocrinology & Metabolism, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom 8 Birmingham Neuro-Ophthalmology, Ophthalmology Department, Queen Elizabeth Hospital, University Hospi
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Snippet	BACKGROUNDIdiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH... BACKGROUND. Idiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that... BACKGROUND Idiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH...
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Title	Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension
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