Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca2+ signaling in a reciprocal manner to leptin: Orexigenic neuronal pathways in the mediobasal hypothalamus

Shinji Muroya, Hisayuki Funahashi, Akihiro Yamanaka, Daisuke Kohno, Kazuhide Uramura, Tadahiro Nambu, Megumi Shibahara, Motoki Kuramochi, Morikuni Takigawa, Masashi Yanagisawa, Takeshi Sakurai, Seiji Shioda, Toshihiko Yada

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195 Scopus citations


Orexin-A and -B (hypocretin-1 and -2) have been implicated in the stimulation of feeding. Here we show the effector neurons and signaling mechanisms for the orexigenic action of orexins in rats. Immunohistochemical methods showed that orexin axon terminals contact with neuropeptide Y (NPY)- and proopiomelanocortin (POMC)-positive neurons in the arcuate nucleus (ARC) of the rats. Microinjection of orexins into the ARC markedly increased food intake. Orexins increased cytosolic Ca2+ concentration ([Ca 2+]i) in the isolated neurons from the ARC, which were subsequently shown to be immunoreactive for NPY. The increases in [Ca 2+]i, were inhibited by blockers of phospholipase C (PLC), protein kinase C (PKC) and Ca2+ uptake into endoplasmic reticulum. The stimulation of food intake and increases in [Ca2+]i in NPY neurons were greater with orexin-A than with orexin-B, indicative of involvement of the orexin-1 receptor (OX1R). In contrast, orexin-A and -B equipotently attenuated [Ca2+]i oscillations and decreased [Ca2+]i levels in POMC-containing neurons. These effects were counteracted by pertussis toxin, suggesting involvement of the orexin-2 receptor and Gi/Go subtypes of GTP-binding proteins. Orexins also decreased [Ca2+]i levels in glucose-responsive neurons in the ventromedial hypothalamus (VMH), a satiety center. Leptin exerted opposite effects on these three classes of neurons. These results demonstrate that orexins directly regulate NPY, POMC and glucose-responsive neurons in the ARC and VMH, in a manner reciprocal to leptin. Orexin-A evokes Ca2+ signaling in NPY neurons via OX1R-PLC-PKC and IP3 pathways. These neural pathways and intracellular signaling mechanisms may play key roles in the orexigenic action of orexins.

Original languageEnglish (US)
Pages (from-to)1524-1534
Number of pages11
JournalEuropean Journal of Neuroscience
Issue number6
StatePublished - Mar 1 2004



  • Arcuate nucleus
  • Feeding
  • Leptin
  • Neuropeptide Y
  • Orexin
  • POMC

ASJC Scopus subject areas

  • Neuroscience(all)

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