leptin and Pseudotumor-Cerebri

The pathogenesis of idiopathic intracranial hypertension (IIH) is poorly understood. Several mechanisms have been suggested, but no one mechanism has been able to account for all manifestations of the disease. Although IIH predominantly affects obese, premenopausal women, little is known about whether or how the obesity contributes to the IIH. Obesity is a heterogeneous condition, consisting of different phenotypes that are influenced by the regional distribution of adipose tissue. This review explores the literature to integrate current knowledge on the relationships between obesity and IIH. The review evaluates the hypotheses that dysregulation of insulin, glucose metabolism, sex hormones, adipokines, glucocorticoids, lipids and free fatty acids in obesity could predispose to IIH. One potential common pathway linking metabolic disorders to the pathogenesis of IHH is a thrombotic tendency due to dysregulation of haemostatic risk factors. This could cause either occult cerebral sinus thrombosis or partial thrombosis of the parasagittal venous lacunae, with subsequent impaired resorption of cerebrospinal fluid and venous hypertension. Investigations that evaluate obesity, fat metabolism, endocrinological dysregulation and thrombotic tendency in patients with IIH are required so that pathogenic mechanisms can be clarified and management strategies in IIH can be improved.

Topics: Adipose Tissue; Blood Glucose; Cerebrospinal Fluid Pressure; Female; Humans; Leptin; Male; Obesity; Phenotype; Pseudotumor Cerebri; Risk Factors; Sex Factors

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.

Topics: Adipocytes; Adipose Tissue; Adult; Biopsy; Blood Glucose; Case-Control Studies; Female; Humans; Insulin; Leptin; Metabolic Diseases; Middle Aged; Obesity; Pseudotumor Cerebri; Young Adult

Topics: Adult; Body Mass Index; Case-Control Studies; Female; Humans; Intracranial Pressure; Leptin; Limit of Detection; Obesity; Pseudotumor Cerebri; Young Adult

The aetiology of idiopathic intracranial hypertension (IIH) is not known, but its association with obesity is well-recognized. Recent studies have linked obesity with abnormalities in circulating inflammatory and adiposity related cytokines. The aim of this study was to characterize adipokine and inflammatory cytokine profiles in IIH.. Paired serum and cerebrospinal fluid (CSF) specimens were collected from 26 patients with IIH and compared to 62 control subjects. Samples were analysed for leptin, resistin, adiponectin, insulin, IL-1beta, IL-6, IL-8 (CXCL8), TNFalpha, MCP-1 (CCL2), hepatocyte growth factor, nerve growth factor and PAI-1 using multiplex bead immunoassays.. CSF leptin was significantly higher in patients with IIH (P = 0.001) compared to controls after correction for age, gender and body mass index (BMI). In the control population, BMI correlated with serum leptin (r = 0.34; P = 0.007) and CSF leptin (r = 0.51; P < 0.0001), but this was not the case for the IIH population. Profiles of other inflammatory cytokines and adipokines did not differ between IIH patients and controls once anthropometric factors had been accounted for.. IIH was characterized by significantly elevated CSF leptin levels which did not correlate with BMI. We suggest that CSF leptin may be important in the pathophysiology of IIH and that obesity in IIH may occur as a result of hypothalamic leptin resistance.

Topics: Adipokines; Adult; Body Mass Index; Case-Control Studies; Cytokines; Drug Resistance; Female; Humans; Hypothalamus; Leptin; Middle Aged; Pseudotumor Cerebri

Idiopathic intracranial hypertension (IIH) occurs predominantly in young, obese women. Weight loss may alleviate symptoms of IIH yet may be difficult to achieve. Ghrelin, a gastric hormone, is involved in normal body weight and appetite regulation. Its levels are elevated in syndromes of overeating and decline in simple obesity. We postulated that fasting plasma ghrelin levels are elevated in IIH patients and that the typical postprandial decline in plasma ghrelin may not occur.. Prospective, observational case-control study.. Prospective study.. University hospital and clinic.. Sixty-five patients with a diagnosis of IIH and 25 obese control patients (screened for IIH symptoms). Patients with intracranial abnormalities or a history of gastric surgery were excluded.. Fasting plasma ghrelin, leptin, and insulin levels were assessed between 8 am and 10 am. Subjects were fed a standard breakfast, and postprandial ghrelin levels were measured 30 minutes later.. Fasting plasma ghrelin levels negatively correlated with body mass index in both IIH subjects (r = -.48) and controls; leptin showed a positive correlation with body mass index in both IIH (r =.59) and controls. Levels were not significantly different between the groups. Postprandial ghrelin declined by 71 +/- 31 (95% CI) pg/ml in the IIH group and 71 +/- 35 (95% CI) pg/ml in the control group.. Plasma ghrelin levels, both fasting and postprandial, do not differ between IIH patients and obese controls. Obese IIH patients should be encouraged to lose weight and referred for medical weight loss management to maximize their chances of alleviating their symptoms.

Topics: Adult; Body Constitution; Body Mass Index; Case-Control Studies; Female; Ghrelin; Growth Hormone; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Peptide Hormones; Prospective Studies; Pseudotumor Cerebri; Weight Loss