A neuron-enriched secreting protein, NELL2 is a highly conserved molecule between rodents and human. With its several functional motifs, NELL2 has been suggested to play a critical role in embryonic neural development and neuronal protection. However, NELL2 function in adulthood brain has not been clearly understood until recently. To uncover NELL2-associated brain physiology in adulthood, we recently performed an experiment ablating hypothalamic NELL2 production over a short time period in adult rats. We observed that NELL2 signaling in brain is tightly associated with an animal’s appetite behavior and metabolism regulation. NELL2 is expressed in several hypothalamic nuclei, including the paraventricular nucleus, ventromedial hypothalamus, and the arcuate nucleus, all of which are known to be important in whole body energy homeostasis. Hypothalamic NELL2 was upregulated by fasting, and removal of hypothalamic NELL2 resulted in reduction of daily appetite behavior under normal chow conditions and without changes in water intake. Therefore, rats with hypothalamic NELL2 ablation showed an attenuated body weight gain compared to the control. These data clearly suggested that NELL2 plays an orexigenic role in metabolism regulation. However, the brain regions involved in NELL2 activity for the regulation of metabolism are still uncertain. Furthermore, the effect of NELL2-specific receptor, and NELL2-dependent cellular signaling on metabolism regulation have not been delineated. Therefore, future studies aiming to challenge these issues are necessary to clearly understand contribution of NELL2 on energy homeostasis.