Nesfatin-1 can cross the blood–brain barrier without saturation.
The receptors within the brain are in the hypothalamus and the solitary nucleus, where nesfatin-1 is believed to be produced via peroxisome proliferator-activated receptors (PPARs). It appears there is  a relationship between nesfatin-1 and cannabinoid receptors. Nesfatin-1-induced inhibition of feeding may be mediated through the inhibition of orexigenic NPY neurons.
Nesfatin/NUCB2 expression has been reported to be modulated by starvation and re-feeding in the Paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the brain. Nesfatin-1 influences the excitability of a large proportion of different subpopulations of neurons located in the PVN. It is also reported that magnocellular oxytocin neurons are activated during feeding, and ICV infusion of oxytocin antagonist increases food intake, indicating a possible role of oxytocin in the regulation of feeding behavior. In addition, it is proposed that feeding-activated nesfatin-1 neurons in the PVN and SON could play an important role in the postprandial regulation of feeding behavior and energy homeostasis.
Nesfatin-1 immunopositive neurons are also located in the arcuate nucleus (ARC). Nesfatin-1 immunoreactive neurons in the ARC are activated by simultaneous injection of ghrelin and desacyl ghrelin, nesfatin-1 may be involved in the desacyl ghrelin-induced inhibition of the orexigenic effect of peripherally administered ghrelin in freely fed rat.
Nesfatin-1 was co-expressed with melanin concentrating hormone (MCH) in tuberal hypothalamic neurons. Nesfatin-1 co-expressed in MCH neurons may play a complex role not only in the regulation of food intake, but also in other essential integrative brain functions involving MCH signaling, ranging from autonomic regulation, stress, mood, cognition to sleep.