Insulin has been shown to have effects not only in the peripheral tissues, but also in the brain particularly in the arcuate nucleus of the hypothalamus to regulate glucose and energy homeostasis. The importance of the central neuropeptide Y (NPY) system in the regulation of appetite and energy metabolism is well established. Although insulin is known to influence NPY expression, the precise physiological role of insulin action in these neuronal cells remains unknown. A closely related peptide, PYY released from L-type cells of the gut, is also expressed in α-cells in the pancreatic islets. It has been shown that application of PYY decreases glucose stimulated insulin secretion from rat and mouse islets. PYY can activate Y1, Y2 and Y5 receptor to regulate feeding and energy balance, however, little is known as to which Y receptor(s) mediate PYY’s effect in the pancreatic islets. We have recently identified that the Y1 receptors are expressed in the β-cells both in mice and humans. In this presentation, I will discuss the role of insulin action in NPY-expressing neurons and provide evidence addressing the role of Y1 receptor in the regulation of β-cell function and how inhibition of this receptor could improve islet transplantation outcome.