The human NPY5 receptor mRNA expresses largely in the central nervous system, and highly expressed in hypothalamic and thalamic nuclei. Neuropeptide Y has a major role in the physiological control of energy homeostasis, and the NPY5 receptor is a prime candidate to mediate some of the effects through metabolic changes such as decreased lipolysis and thermogenesis, as well as hyperphagia. NPY5 is involved in both spontaneous as well as NPY-stimulated food intake and in NPY-induced reduction of blood glucose concentrations. NPY5 also plays an important role in neuroendocrine functions. It mediates the inhibitory effects of NPY on the HPT axis, and may function as part of an endogenous stress-sensing system to mediate social anxiety and motivational deficits. In addition, NPY5 may be involved in NPY-induced ischemic angiogenesis and opioid dependence and withdrawal.