Brain insulin: regulation, mechanisms of action and functions.

1. While many questions remained unanswered, it is now well documented that, contrary to earlier views, insulin is an important neuromodulator, contributing to neurobiological processes, in particular energy homeostasis and cognition. A specific role on cognitive functions related to feeding is proposed, and it is suggested that brain insulin from different sources might be involved in the above vital functions in health and disease. 2. A molecule identical to pancreatic insulin, and specific insulin receptors, are found widely distributed in the central nervous system networks related to feeding, reproduction, or cognition. 3. The actions of insulin in the central nervous system may be under both multilevel and multifactorial controls. The amount of blood insulin reaching the brain, brain insulin stores and secretion, potential local biosynthesis and degradation of the peptide, and insulin receptors and signal transduction can be affected by metabolic factors induced by nutrients, hormones, neurotransmitters, and regulatory peptides, peripherally or in the central nervous system. 4. Glucose and serotonin regulate insulin directly in the hypothalamus and may be of importance for its biological effects. Central mechanisms regulating glucose-induced insulin secretion show some analogy with the mechanisms operating in the pancreas. 5. A cross-talk between insulin and leptin receptors has been observed in the brain, and a regulation of central insulin actions, potentially via serotonin modulation, by leptin, galanin, melancortins, and neuropeptide Y (NPY) is suggested. 6. A more complete knowledge of the biological role of insulin in brain function and dysfunction, and of the regulatory mechanisms involved in these processes, constitutes a real advancement in the understanding of the pathophysiology of metabolic and mental diseases and could lead to important medical benefits.