Leptin suppresses ghrelin-induced activation of neuropeptide Y neurons in the arcuate nucleus via phosphatidylinositol 3-kinase- and phosphodiesterase 3-mediated pathway

Daisuke Kohno, Masanori Nakata, Fumihiko Maekawa, Ken Fujiwara, Yuko Maejima, Motoki Kuramochi, Takuya Shimazaki, Hideyuki Okano, Tatsushi Onaka, Toshihiko Yada

Research output: Contribution to journalArticle

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Abstract

Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) play a central role in stimulation of feeding. They sense and integrate peripheral and central signals, including ghrelin and leptin. However, the mechanisms of interaction of these hormones in NPY neurons are largely unknown. This study explored the interaction and underlying signaling cross talk between ghrelin and leptin in NPY neurons. Cytosolic Ca2+ concentration ([Ca 2+]i) in single neurons isolated from ARC of adult rats was measured by fura-2 microfluorometry. Ghrelin increased [Ca 2+]i in 31% of ARC neurons. The [Ca2+] i increases were inhibited by blockers of phospholipase C, adenylate cyclase, and protein kinase A. Ghrelin-induced [Ca2+]i increases were suppressed by subsequent administration of leptin. Fifteen of 18 ghrelin-activated, leptin-suppressed neurons (83%) contained NPY. Leptin suppression of ghrelin responses was prevented by pretreatment with inhibitors of phosphatidylinositol 3-kinase and phosphodiesterase 3 (PDE3) but not MAPK. ATP-sensitive potassium channel inhibitors and activators did not prevent and mimic leptin suppression, respectively. Although leptin phosphorylated signal-transducer and activator of transcription 3 (STAT3) in NPY neurons, neither STAT3 inhibitor nor genetic STAT3 deletion altered leptin suppression of ghrelin responses. Furthermore, orexigenic effect of intracerebroventricular ghrelin in rats was counteracted by leptin in a PDE3-dependent manner. These findings indicate that ghrelin increases [Ca2+]i via mechanisms depending on phospholipase C and adenylate cyclase-PKA pathways in ARC NPY neurons and that leptin counteracts ghrelin responses via a phosphatidylinositol 3-kinase-PDE3 pathway. This interaction may play an important role in regulating ARC NPY neuron activity and, thereby, feeding.

Original languageEnglish
Pages (from-to)2251-2263
Number of pages13
JournalEndocrinology
Volume148
Issue number5
DOIs
Publication statusPublished - 2007 May

Fingerprint

Phosphatidylinositol 3-Kinase
Arcuate Nucleus of Hypothalamus
Ghrelin
Neuropeptide Y
Phosphoric Diester Hydrolases
Leptin
Neurons
STAT3 Transcription Factor
Type C Phospholipases
Adenylyl Cyclases
Phosphodiesterase 3 Inhibitors
Cytophotometry
Adenylate Kinase
KATP Channels
Cyclic AMP-Dependent Protein Kinases

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Leptin suppresses ghrelin-induced activation of neuropeptide Y neurons in the arcuate nucleus via phosphatidylinositol 3-kinase- and phosphodiesterase 3-mediated pathway. / Kohno, Daisuke; Nakata, Masanori; Maekawa, Fumihiko; Fujiwara, Ken; Maejima, Yuko; Kuramochi, Motoki; Shimazaki, Takuya; Okano, Hideyuki; Onaka, Tatsushi; Yada, Toshihiko.

In: Endocrinology, Vol. 148, No. 5, 05.2007, p. 2251-2263.

Research output: Contribution to journalArticle

Kohno, Daisuke ; Nakata, Masanori ; Maekawa, Fumihiko ; Fujiwara, Ken ; Maejima, Yuko ; Kuramochi, Motoki ; Shimazaki, Takuya ; Okano, Hideyuki ; Onaka, Tatsushi ; Yada, Toshihiko. / Leptin suppresses ghrelin-induced activation of neuropeptide Y neurons in the arcuate nucleus via phosphatidylinositol 3-kinase- and phosphodiesterase 3-mediated pathway. In: Endocrinology. 2007 ; Vol. 148, No. 5. pp. 2251-2263.
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abstract = "Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) play a central role in stimulation of feeding. They sense and integrate peripheral and central signals, including ghrelin and leptin. However, the mechanisms of interaction of these hormones in NPY neurons are largely unknown. This study explored the interaction and underlying signaling cross talk between ghrelin and leptin in NPY neurons. Cytosolic Ca2+ concentration ([Ca 2+]i) in single neurons isolated from ARC of adult rats was measured by fura-2 microfluorometry. Ghrelin increased [Ca 2+]i in 31{\%} of ARC neurons. The [Ca2+] i increases were inhibited by blockers of phospholipase C, adenylate cyclase, and protein kinase A. Ghrelin-induced [Ca2+]i increases were suppressed by subsequent administration of leptin. Fifteen of 18 ghrelin-activated, leptin-suppressed neurons (83{\%}) contained NPY. Leptin suppression of ghrelin responses was prevented by pretreatment with inhibitors of phosphatidylinositol 3-kinase and phosphodiesterase 3 (PDE3) but not MAPK. ATP-sensitive potassium channel inhibitors and activators did not prevent and mimic leptin suppression, respectively. Although leptin phosphorylated signal-transducer and activator of transcription 3 (STAT3) in NPY neurons, neither STAT3 inhibitor nor genetic STAT3 deletion altered leptin suppression of ghrelin responses. Furthermore, orexigenic effect of intracerebroventricular ghrelin in rats was counteracted by leptin in a PDE3-dependent manner. These findings indicate that ghrelin increases [Ca2+]i via mechanisms depending on phospholipase C and adenylate cyclase-PKA pathways in ARC NPY neurons and that leptin counteracts ghrelin responses via a phosphatidylinositol 3-kinase-PDE3 pathway. This interaction may play an important role in regulating ARC NPY neuron activity and, thereby, feeding.",
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AU - Maekawa, Fumihiko

AU - Fujiwara, Ken

AU - Maejima, Yuko

AU - Kuramochi, Motoki

AU - Shimazaki, Takuya

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