Many factors and pathways have been implicated in the regulation of appetite and energy homeostasis, however, none of them are as central and essential as the NPY system. NPY is a complex system consisting of 3 ligand genes NPY, peptide YY (PYY) and pancreatic polypeptide (PP) and at least 5 different receptors (Y1, Y2, Y4, Y5 and y6). Whereas central NPY is known to stimulate appetite and feeding behaviour, the mostly peripherally expressed family members PYY and PP have the opposite effect and have been identified as potent satiety factors. Negative energy balance, leads to increased hypothalamic NPY expression and the activation of appetite stimulatory pathways and other feeding related behaviours. However, NPY causes also neuroendocrine and metabolic changes which favour energy storage including decreased thermogenesis, hyperinsulinemia, insulin hyper-responsiveness in white adipose tissue, activation of the hypothalamo-pituitary-adrenal axis, and decreased activity of the hypothalamo-pituitary-thyrotropic, -somatotropic, and –gonadotropic axes. Furthermore, whole body homeostasis does not only involve the regulation of fat and lean mass but also that of bone mass and coordinating this to bodyweight, e.g. larger body mass requires stronger bones. Recently, we have identified the critical role of the NPY system in the regulation of bone formation with reduced central and peripheral Y-receptor signalling leading to elevation in bone formation and bone volume. In addition, elevation in bodyweight and the subsequent development of obesity are associated with low-grade inflammation likely leading to insulin resistance in this tissue. Importantly, the NPY system also plays a critical role in modulating the immune system and thereby influencing particular stress related immune responses. New outcomes of the analysis of various transgenic models from the NPY family in regards to the regulation of energy and bone homeostasis with a particular focus on stress-induced changes will be presented.