Determining the role of novel metabolic pathways in driving intracranial pressure reduction after weight loss.

Idiopathic intracranial hypertension, a disease classically occurring in women with obesity, is characterized by raised intracranial pressure. Weight loss leads to the reduction in intracranial pressure. Additionally, pharmacological glucagon-like peptide-1 agonism reduces cerebrospinal fluid secretion and intracranial pressure. The potential mechanisms by which weight loss reduces intracranial pressure are unknown and were the focus of this study. Meal stimulation tests (fasted plasma sample, then samples at 15, 30, 60, 90 and 120 min following a standardized meal) were conducted pre- and post-bariatric surgery [early (2 weeks) and late (12 months)] in patients with active idiopathic intracranial hypertension. Dynamic changes in gut neuropeptides (glucagon-like peptide-1, gastric inhibitory polypeptide and ghrelin) and metabolites (untargeted ultra-high performance liquid chromatography-mass spectrometry) were evaluated. We determined the relationship between gut neuropeptides, metabolites and intracranial pressure. Eighteen idiopathic intracranial hypertension patients were included [Roux-en-Y gastric bypass (RYGB) n = 7, gastric banding n = 6 or sleeve gastrectomy n = 5]. At 2 weeks post-bariatric surgery, despite similar weight loss, RYGB had a 2-fold (50%) greater reduction in intracranial pressure compared to sleeve. Increased meal-stimulated glucagon-like peptide-1 secretion was observed after RYGB (+600%) compared to sleeve (+319%). There was no change in gastric inhibitory polypeptide and ghrelin. Dynamic changes in meal-stimulated metabolites after bariatric surgery consistently identified changes in lipid metabolites, predominantly ceramides, glycerophospholipids and lysoglycerophospholipids, which correlated with intracranial pressure. A greater number of differential lipid metabolites were observed in the RYGB cohort at 2 weeks, and these also correlated with intracranial pressure. In idiopathic intracranial hypertension, we identified novel changes in lipid metabolites and meal-stimulated glucagon-like peptide-1 levels following bariatric surgery which were associated with changes in intracranial pressure. RYGB was most effective at reducing intracranial pressure despite analogous weight loss to gastric sleeve at 2 weeks post-surgery and was associated with more pronounced changes in these metabolite pathways. We suggest that these novel perturbations in lipid metabolism and glucagon-like peptide-1 secretion are mechanistically important in driving a reduction in intracranial pressure following weight loss in patients with idiopathic intracranial hypertension. Therapeutic targeting of these pathways, for example with glucagon-like peptide-1 agonist infusion, could represent a therapeutic strategy.
Competing Interests: S.P.M. reports consultancy fees and advisory boards from Invex Therapeutics, and educational fees from Heidelberg Engineering during the conduct of the study, outside the submitted work. She has received Honoria for education and advisory boards from Chugai-Roche Ltd, Gensight, Janssen, Allergan, Santen, Teva, Roche and Neurodiem. O.G. reports scientific consultancy fees from Invex Therapeutics during the conduct of the study, outside the submitted work. A.Y. reports receiving speaker fees for educational talks from Teva, UK outside the submitted work. A.J.S. reports consulting fees and stockholding with Invex Therapeutics, during the conduct of the study, outside of the submitted work. She has received honoraria for education and advisory boards from Allergan, Amgen, Novartis and Cheisi outside the submitted work. A.A.T. reports grants from Novo Nordisk, personal fees from Novo Nordisk, non-financial support from Novo Nordisk, personal fees from Eli Lilly, non-financial support from Eli Lilly, personal fees from Janssen, personal fees from AZ, non-financial support from AZ, non-financial support from Impeto medical, non-financial support from Resmed, non-financial support from Aptiva, personal fees from BI, non-financial support from BI, personal fees from BMS, non-financial support from BMS, personal fees from NAPP, non-financial support from NAPP, personal fees from MSD, non-financial support from MSD, personal fees from Nestle, personal fees from Gilead, grants from Sanofi and personal fees from Sanofi outside the submitted work. A.A.T. is currently an employee of Novo Nordisk. Novo Nordisk had no role in this project. All other authors declare no competing interests.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)