The neuropeptide Y (NPY) system--comprising of neuropeptide Y, peptide YY, pancreatic polypeptide and the corresponding Y receptors through which they act (Y1, Y2, Y4, Y5 and y6)--is well known for its role in the regulation of energy homeostasis and associated processes. Dysfunctions of the system have been implicated in human diseases such as obesity and cancer, raising the possibility that correction of the system may provide therapeutic benefits for these diseases. In addition to the regulation of appetite and satiety that has attracted most attention during the past years, insight has also been gained into the critical role of NPY in the control of energy expenditure, oxidative fuel selection and bone metabolism. Studies using conditional knockout models further shed light on the central versus peripheral, and hypothalamic versus extra-hypothalamic mechanisms of these regulatory effects of NPY. Moreover, a role of NPY family peptides and Y receptors in modulating the growth of tumours has emerged. These findings provide the basis for novel NPY system-targeted strategies to treat obesity as well as cancer. Such strategies include modifying both sides of the energy balance equation--energy intake versus energy expenditure--to achieve a greater weight/fat loss by particularly modulating peripheral Y receptor(s) to ameliorate metabolic conditions without interfering with central functions of Y receptors. In addition, targeting multiple Y receptors and/or multiple systems involved in the regulation of energy balance will have greater beneficial effects. However, long-term interference with the NPY system to target obesity or cancer related aspects needs to consider potential side effects on bone health.
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