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Leptin Suppresses Ghrelin-Induced Activation of Neuropeptide Y Neurons in the Arcuate Nucleus via Phosphatidylinositol 3-Kinase- and Phosphodiesterase 3-Mediated Pathway

Divisions of Integrative Physiology (D.K., M.N., F.M., K.F., Y.M., M.K., T.Y.) and Neurophysiology (T.O.), Department of Physiology, Division of Histology and Cell Biology (K.F.), Department of Anatomy, and Department of Neuropsychiatry (M.K.), Jichi Medical University School of Medicine, Tochigi 329-0498, Japan; and Department of Physiology (T.S., H.O.), Keio University School of Medicine, Tokyo 160-8582, Japan

Address all correspondence and requests for reprints to: Dr. Toshihiko Yada, Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Tochigi 329-0498, Japan. E-mail: tyada{at}jichi.ac.jp.

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 ([Ca²⁺]_i) in single neurons isolated from ARC of adult rats was measured by fura-2 microfluorometry. Ghrelin increased [Ca²⁺]_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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