Obesity and sex hormones interact to promote CSF hyperdynamics in an obese rodent model of idiopathic intracranial hypertension

Idiopathic intracranial hypertension (IIH) is a syndrome exhibiting elevated intracranial pressure (ICP), visual disturbances, and severe headache. IIH primarily affects young obese women, though it can occur in individuals of any age, BMI, and sex. IIH is characterized by systemic metabolic dysregulation with a profile of increased androgen hormones. However, the contributions of obesity/hormonal perturbations to cerebrospinal fluid (CSF) dynamics remains unresolved. We employed obese female Zucker rats and adjuvant testosterone to reveal IIH causal drivers. ICP and CSF dynamics were determined with in vivo experimentation and magnetic resonance imaging, testosterone levels assessed with mass spectrometry, and choroid plexus function revealed with transcriptomics. Obese rats had undisturbed CSF testosterone levels and no changes in ICP or CSF dynamics. Chronic adjuvant testosterone treatment of obese rats elevated the CSF secretion rate, although with no effect on the ICP, due to the elevated CSF drainage capacity of these rats. Obesity in itself therefore does not suffice to recapitulate the IIH symptoms, but modulation of CSF dynamics comes about with adjuvant testosterone treatment, mimicking the androgen excess observed in female IIH patients. Obesity-induced androgen dysregulation may thus play a crucial role in the disease mechanism of IIH.特发性颅内高压（Idiopathic Intracranial Hypertension, IIH）是一类以颅内压（Intracranial Pressure, ICP）升高、视觉障碍及剧烈头痛为特征的综合征。IIH主要累及年轻肥胖女性，但任何年龄、体重指数（Body Mass Index, BMI）与性别的个体均可发病。IIH以全身代谢失调为特征，伴随雄激素水平升高的表型。然而，肥胖/激素紊乱对脑脊液（Cerebrospinal Fluid, CSF）动力学的影响仍未明确。本研究选用肥胖雌性Zucker大鼠并辅以睾酮治疗，以揭示IIH的致病驱动因素。研究通过体内实验与磁共振成像（Magnetic Resonance Imaging, MRI）检测ICP与脑脊液动力学，采用质谱法（Mass Spectrometry）评估睾酮水平，并通过转录组学（Transcriptomics）解析脉络丛功能。结果显示，肥胖大鼠的脑脊液睾酮水平未受干扰，颅内压与脑脊液动力学亦无异常变化。对肥胖大鼠施以长期辅助睾酮干预后，虽因该类大鼠脑脊液引流能力升高而未对颅内压造成影响，但其脑脊液分泌速率却有所提升。因此，单纯肥胖并不足以重现IIH的症状，而辅助睾酮治疗可调节脑脊液动力学，模拟女性IIH患者体内所观测到的雄激素过量状态。由此可见，肥胖诱导的雄激素失调可能在IIH的发病机制中发挥关键作用。