Role of NPY in energy intake and expenditure. cNPY: NPY in the central nervous system; pNPY: Peripheral NPY; BBB: Blood brain barrier; Hypo: hypothalamus. The cNPY stimulates food intake mainly via NPYR1 and NPYR5 to increase energy intake. Additionally, through the hypothalamus-SNS-adipose axis, NPY reduces sympathetic nervous system (SNS) outflow, which promotes white adipose tissue (WAT) deposition by enhancing adipogenesis and inhibiting lipolysis, as well as inhibiting brown adipose tissue (BAT) deposition and associated nonshivering thermogenesis. The same effects in WAT were achieved by peripheral NPY via different signaling pathways. This collectively leads to energy storage in adipose tissue. Adipose-hypothalamus crosstalk serves as a feedback loop via sensory inflow that informs the brain of the long-term peripheral energy status so that the brain can make the necessary adjustment. Numerous adipokines, hormones, and appetite regulating factors have been identified that play an important role in adjusting energy balance through the hypothalamus either by directly affecting food intake or regulating adiposity through SNS outflow, such as leptin, NPY, and UCP1. NPY is more abundant in the central nervous system as compared to the peripheral system. Whether and how it crosses the blood brain barrier is critical for understanding its role in energy regulation.