Exercise has multiple beneficial effects including improving peripheral insulin sensitivity, improving central function such as memory, and restoring a dysregulated blood-brain barrier (BBB). Central nervous system (CNS) insulin resistance is a common feature of cognitive impairment, including Alzheimer’s disease. Delivery of insulin to the brain can improve memory. Endogenous insulin must cross the BBB to directly act within the CNS and this transport system can be affected by various physiological states and serum factors. Therefore, the current study sought to investigate whether exercise could enhance insulin BBB transport as a mechanism for the underlying benefits of exercise on cognition. We investigated radioactive insulin BBB pharmacokinetics following an acute bout of exercise in young, male and female CD-1 mice. In addition, we investigated changes in serum levels of substrates that are known to affect insulin BBB transport. Finally, we measured the basal level of a downstream protein involved in insulin receptor signaling in various brain regions as well as muscle. We found insulin BBB transport in males was greater following exercise, and in males and females to both enhance the level of insulin vascular binding and alter CNS insulin receptor signaling, independent of changes in serum factors known to alter insulin BBB transport.

NEW & NOTEWORTHY Central nervous system (CNS) insulin and exercise are beneficial for cognition. CNS insulin resistance is present in Alzheimer’s disease. CNS insulin levels are regulated by transport across the blood-brain barrier (BBB). We show that exercise can enhance insulin BBB transport and binding of insulin to the brain’s vasculature in mice. There were no changes in serum factors known to alter insulin BBB pharmacokinetics. We conclude exercise could impact cognition through regulation of insulin BBB transport.