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. Overall design: Differential expression analysis of female lean and obese Zucker rats, treated with vehicle (VEH) or testosterone (TT)