Paraventricular NUCB2/nesfatin-1 rises in synchrony with feeding suppression during early light phase in rats

Obesity often results from hyperphagia and involves rhythm disorder. Circadian feeding pattern is suggested to be implicated in energy homeostasis while its disorder in obesity. However, the mechanism underlying circadian feeding is little known. PVN is considered a regulatory center for feeding and circadian activities of hormone release and autonomic nerve. Nucleobindin2 (NUCB2) and its processing product nesfatin-1 (NUCB2/nesfatin-1) are localized in the hypothalamic paraventricular nucleus (PVN) and implicated in regulation of feeding. This study aimed to clarify whether the PVN NUCB2/nesfatin-1 expression exhibits diurnal rhythm and, if so, whether it is related to circadian feeding. Here we show that NUCB2 mRNA expression in the PVN rises during early light phase (LP) in parallel with suppression of food intake. Immunoneutralization of PVN NUCB2/nesfatin-1 with anti-nesfatin-1 IgG during LP, but not dark phase, increased food intake. PVN-selective shRNA-induced knockdown of NUCB2 mRNA expression elevated food intake. Furthermore, the rise of PVN NUCB2 mRNA during LP was blunted in Zucker-fatty obese rats which exhibited LP-preferential hyperphagia. The increases in food intake during LP and 24h were significantly corrected by intracerebroventricular injection of nesfatin-1 during LP. These results reveal the diurnal rhythm of PVN NUCB2 mRNA expression characterized by early LP rise, which may serve as a factor to limit LP food intake, contributing to circadian feeding. Furthermore, impaired NUCB2/nesfatin-1 rhythm may be related to dysregulated feeding pattern and hyperphagia in Zucker-fatty rats.