The contribution of hypothalamic neuropeptide Y to age-dependent body weight changes

Middle-aged obesity and age-related anorexia leading to sarcopenia present a major public health burden. Similar age-associated patterns are observed across mammalian species, suggesting the involvement of conserved regulatory mechanisms. Age-dependent biphasic shifts in the balance between anabolic and catabolic signals of the adipose tissue–hypothalamus axis may contribute to both trends. Among hypothalamic mediators, neuropeptide Y (NPY) is a key anabolic (orexigenic and hypometabolic) peptide. This review summarizes current evidence on age-dependent changes in the effects of NPY on energy homeostasis. Activity of NPY shows a midlife increase in animal studies, promoting age-related obesity, whereas its decline in old age — demonstrated in both experimental and human studies — may be involved in aging anorexia and sarcopenia. The activity of catabolic neuropeptides that inhibit the NPY system changes in an opposite pattern across the lifespan. Age-related changes should be considered in drug development targeting NPY and its receptors.