Nesfatin-1-Regulated Oxytocinergic Signaling in the Paraventricular Nucleus Causes Anorexia through a Leptin-Independent Melanocortin Pathway

The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we s...

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Bibliographic Details
Published in:Cell metabolism 2009-11, Vol.10 (5), p.355-365
Main Authors: Maejima, Yuko, Sedbazar, Udval, Suyama, Shigetomo, Kohno, Daisuke, Onaka, Tatsushi, Takano, Eisuke, Yoshida, Natsu, Koike, Masato, Uchiyama, Yasuo, Fujiwara, Ken, Yashiro, Takashi, Horvath, Tamas L., Dietrich, Marcelo O., Tanaka, Shigeyasu, Dezaki, Katsuya, Hashimoto, Koushi, Shimizu, Hiroyuki, Nakata, Masanori, Mori, Masatomo, Yada, Toshihiko
Format: Article
Language:English
Subjects:
Animals
Anorexia - metabolism
Autocrine Communication
Calcium-Binding Proteins
DNA-Binding Proteins
HUMDISEASE
Leptin - metabolism
Melanocortins - metabolism
Mice
Nerve Tissue Proteins - metabolism
Neuroendocrine Cells - metabolism
Oxytocin - metabolism
Paracrine Communication
Paraventricular Hypothalamic Nucleus - metabolism
Pro-Opiomelanocortin - metabolism
Rats
Rats, Zucker
Signal Transduction - physiology
Solitary Nucleus - metabolism
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Summary:The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we show that central injection of nesfatin-1 activates the PVN and brain stem nucleus tractus solitarius (NTS). In the PVN, nesfatin-1 targets both magnocellular and parvocellular oxytocin neurons and nesfatin-1 neurons themselves and stimulates oxytocin release. Immunoelectron micrographs reveal nesfatin-1 specifically in the secretory vesicles of PVN neurons, and immunoneutralization against endogenous nesfatin-1 suppresses oxytocin release in the PVN, suggesting paracrine/autocrine actions of nesfatin-1. Nesfatin-1-induced anorexia is abolished by an oxytocin receptor antagonist. Moreover, oxytocin terminals are closely associated with and oxytocin activates pro-opiomelanocortin neurons in the NTS. Oxytocin induces melanocortin-dependent anorexia in leptin-resistant Zucker-fatty rats. The present results reveal the nesfatin-1-operative oxytocinergic signaling in the PVN that triggers leptin-independent melanocortin-mediated anorexia.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2009.09.002