A budget for brain metabolic water production by glucose catabolism during rest, rises in activity and sleep

Maintaining brain fluid homeostasis is of critical importance for creating a stable environment conducive to optimal neuronal functioning, nutrient distribution, and waste product removal. In this study, we employed previously published data on brain oxygen and glucose consumption in awake rodents or humans to quantify the metabolic water production associated with distinct pathways of glucose metabolism. It is predicted that neuronal mitochondria are the primary source of metabolic water at rest, resulting in a continuous efflux into the cytosol, interstitial fluid, and cerebrospinal fluid. Net metabolic water production is predicted to be reduced by increases in activity due to a shift in metabolism from glucose oxidation to include glycolysis in neurons and ATP hydrolysis by the major cation pumps, which involves water consumption (ATP + H₂O → ADP + Pi). In comparison, glycogenolysis, which occurs concurrently with the activation of astrocytes, potentially represents a major but previously unidentified contributor to metabolic water. Metabolic water production is dependent on the state of the brain, with a reduction of 30-40% occurring during deep sleep. Our estimates indicate that metabolic water functions as a conduit for interstitial fluid production within the brain, enabling flexible and efficient distribution of fluid that flows seamlessly from the parenchyma to the subarachnoid space and lymphatic vessels to facilitate the removal of brain waste, independent of the glymphatic system.