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 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.
Maejima
Yuko
Y
Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498, Japan.
Sedbazar
Udval
U
Suyama
Shigetomo
S
Kohno
Daisuke
D
Onaka
Tatsushi
T
Takano
Eisuke
E
Yoshida
Natsu
N
Koike
Masato
M
Uchiyama
Yasuo
Y
Fujiwara
Ken
K
Yashiro
Takashi
T
Horvath
Tamas L
TL
Dietrich
Marcelo O
MO
Tanaka
Shigeyasu
S
Dezaki
Katsuya
K
Oh-I
Shinsuke
S
Hashimoto
Koushi
K
Shimizu
Hiroyuki
H
Nakata
Masanori
M
Mori
Masatomo
M
Yada
Toshihiko
T
D000818:Animals; D000855:Anorexia / Q000378:metabolism; D019898:Autocrine Communication; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D020738:Leptin / Q000378:metabolism; D053486:Melanocortins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D055099:Neuroendocrine Cells / Q000378:metabolism; D000080866:Nucleobindins; D010121:Oxytocin / Q000378:metabolism*; D019899:Paracrine Communication; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000502:physiology*; D017552:Solitary Nucleus / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D020738:Leptin; D053486:Melanocortins; D009419:Nerve Tissue Proteins; C000630651:Nucb1 protein, mouse; C000630652:Nucb1 protein, rat; D000080866:Nucleobindins; D010121:Oxytocin; D011333:Pro-Opiomelanocortin