High consumption of fructose has paralleled an explosion in metabolic disorders including obesity and type 2 diabetes. Even more problematic, sustained consumption of fructose is perceived as a threat for brain function and development of neurological disorders. The action of fructose on peripheral organs is an excellent model to understand how systemic physiology impacts the brain. Given the recognized action of fructose on liver metabolism, here we discuss mechanisms by which fructose can impact the brain by interacting with liver and other organs. The interaction between peripheral and central mechanisms is a suitable target to reduce the pathophysiological consequences of neurological disorders.