First characterization of metabolomic and lipidomic exchange over the healthy human brain

The energy turnover and metabolic flexibility of the human brain extend beyond a primary reliance on carbohydrates and oxygen. Building on work in anesthetized patients with cerebrovascular pathology, we quantified trans-cerebral arteriovenous differences in healthy humans to isolate and characterize the most abundant cerebral metabolite and lipid species. We observed a net release of acylcarnitine from the cerebral circulation, indicating that these species are active in mitochondrial fatty acid {beta}-oxidation occurring in the healthy resting brain. Furthermore, a strong association was apparent between variability in the brains respiratory quotient (RQ) and activity within the purine salvage pathway, particularly with the uptake of guanosine monophosphate. In a larger sample size (n = 210), we further established that biological variability around an RQ of 1.0 - typically interpreted as exclusive carbohydrate oxidation - coincides with coordinated arteriovenous shifts in metabolomic and lipidomic pathways. The variability is not only visible through complex omics pathways, but is also strongly related to the oxygen carbohydrate index of the brain, further supporting that energy substrates other than glucose are exchanged and oxidized across the brain. These findings reveal substantial versatility and redundancy in how the healthy brain maintains its high energetic demands through flexible, interconnected metabolic and lipidomic networks.