The central nervous system is essential in maintaining energy and glucose homeostasis. In both animals and humans, efficient cerebral insulin signalling is a pivotal control element in these pathophysiological processes. The action of insulin in the brain is under a multilevel control via metabolic, endocrine and neural signals induced by nutrients, integrated mainly by the hypothalamus. Of particular interest is the interaction of insulin with the anabolic and catabolic neuroregulators. The anorexic peptides insulin, leptin and the neurotransmitter serotonin share common signalling pathways involved in food intake, in particular the insulin receptor substrate, phosphatidylinositol-3-kinase (PI3K) pathway. The dialogue of neurotransmitters and peptides via this signalling pathway is potentially of major importance in the pathophysiology of the brain in general and specifically in the regulation of feeding behaviour. At this time, a new concept in the aetiopathology of type 2 diabetes is immerging. This concept proposes that the combination of defective pancreatic beta-cell function and insulin resistance not only in classical insulin target tissues but in every tissue, contributes to the onset of the disease. It highlights the importance of the disruption of cerebral insulin signal transmission and its direct relation to metabolic diseases. Impaired brain insulin signalling, a link coupling obesity to diabetes, may be related to either genetic factors, or environmental factors such as stress, over or under-feeding and unbalanced diets: such factors may work either independently or in concert. Current approaches used for the prevention and treatment of type 2 diabetes are not adequately effective. Most of the anti-diabetic therapies induce many adverse effects, in particular obesity, and thus may initiate a vicious cycle of problems. In order to develop new, more efficient, preventive and therapeutic strategies for metabolic pathologies, there is an urgent need for increased understanding of the complexity of insulin signalling in the brain and on the interactive, central and peripheral effects of insulin.