Central nervous system (CNS) insulin signaling regulates energy and glucose homeostasis by acting on hypothalamic neurocircuits and higher brain circuits such as the dopaminergic system. However, overnutrition, obesity, and type 2 diabetes mellitus (T2DM) induce insulin resistance selectively in different regions of the brain, thereby impairing energy homeostasis and augmenting disease progression. Moreover, fetal hyperinsulinemia in response to maternal overnutrition, obesity, and diabetes disrupts hypothalamic neurocircuit development and predisposes to metabolic disorders later in life. In light of the current obesity and diabetes epidemic, we review the molecular basis of insulin action and resistance in the CNS, mechanisms which are causal to the development of these metabolic disorders, both in the neonate and in the adult.
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