Systemic and adipocyte transcriptional and metabolic dysregulation in Idiopathic Intracranial Hypertension.
Westgate CS., Botfield HF., Alimajstorovic Z., Yiangou A., Walsh M., Smith G., Singhal R., Mitchell JL., Grech O., Markey KA., Hebenstreit D., Tennant DA., Tomlinson JW., Mollan SP., Ludwig C., Akerman I., Lavery GG., Sinclair AJ.
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 to 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 towards depot-specific lipogenesis. CONCLUSIONS: 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 improving cardiovascular outcomes. FUNDING: This study was supported by the National Institute of Health Research UK (NIHR-CS-011-028), the Medical Research Council UK (MR/K015184/1) and the Midlands Neuroscience Teaching and Research Fund.