The insulin resistant brain: impact on whole-body metabolism and body fat distribution

Insulin exerts its actions not only on peripheral organs but is also transported into the brain where it performs distinct functions in various brain regions. This review highlights recent advancements in our understanding of insulin’s actions within the brain, with a specific emphasis on investigations in humans. It summarises current knowledge on the transport of insulin into the brain. Subsequently, it showcases robust evidence demonstrating the existence and physiological consequences of brain insulin action, while also introducing the presence of brain insulin resistance in humans. This pathophysiological condition goes along with an impaired acute modulation of peripheral metabolism in response to brain insulin action, particularly in the postprandial state. Furthermore, brain insulin resistance has been associated with long-term adiposity and an unfavourable adipose tissue distribution, thus implicating it in the pathogenesis of subgroups of obesity and (pre)diabetes that are characterised by distinct patterns of body fat distribution. Encouragingly, emerging evidence suggests that brain insulin resistance could represent a treatable entity, thereby opening up novel therapeutic avenues to improve systemic metabolism and enhance brain functions, including cognition. The review closes with an outlook towards prospective research directions aimed at further elucidating the clinical implications of brain insulin resistance. It emphasises the critical need to establish feasible diagnostic measures and effective therapeutic interventions. Graphical Abstract