Brain insulin signalling in metabolic homeostasis and disease

Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus. This Review critically evaluates the studies that support and refute the role of brain insulin in systemic nutrient partitioning. The authors discuss the role of brain insulin in metabolic control and the contribution of brain insulin resistance to metabolic disease and assess the therapeutic potential of enhancing or restoring brain insulin signalling in metabolic disease.