Role of ARC NPY neurons in energy homeostasis

Neuropeptide Y (NPY) is one of the most abundant and widely distributed neurotransmitters in the mammalian brain and appears to be an important regulatory peptide in both the central and peripheral nervous systems. The arcuate nucleus (ARC) is the major site of expression for NPY within neurons in the hypothalamus. The most noticeable effect of NPY is the stimulation of feeding. To date, six NPY receptor subtypes have been cloned and pharmacologically characterized, and there is evidence for further NPY receptor subtypes. The recent isolation and cloning of a rat NPY receptor with the required pharmacology for the feeding response, called the Y(5) receptor, has led to the suggestion that this is the "feeding" receptor. There is, however, still controversy as to whether the Y(5) receptor represents the true "feeding" receptor, since selective Y(1) receptor antagonists are capable of antagonizing NPY-induced hyperphagia. It also is possible that another, as yet unidentified, NPY receptor subtype(s) may mediate the effects of NPY on energy balance. The potency and behavioral specificity of NPY on feeding and its ability to induce obesity, together with the evidence that ARC-NPY neurons operate homeostatically to counteract energy deficits, all suggest that the ARC-PVN projection is important in regulating energy balance. The next few years will tell us whether or not these important physiological lessons will be successfully translated into a safe and effective form of therapy for human obesity.