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The Journal of Neuroscience, September 21, 2005, 25(38):8657-8664; doi:10.1523/JNEUROSCI.2739-05.2005

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Cellular/Molecular
Insulin Inhibits Neuropeptide Y Gene Expression in the Arcuate Nucleus through GABAergic Systems

Ikuko Sato,¹ Hiroshi Arima,¹ Noriyuki Ozaki,² Minemori Watanabe,¹ Motomitsu Goto,¹ Masayuki Hayashi,¹ Ryouichi Banno,¹ Hiroshi Nagasaki,¹ and Yutaka Oiso¹

¹Department of Endocrinology and Diabetes, Field of Internal Medicine, and ²Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan

Neuropeptide Y (NPY) in the arcuate nucleus is an orexigenic hormone of which levels are regulated by humoral as well as neural signals. In this study, we examined the regulation of NPY gene expression in the arcuate nucleus in hypothalamic organotypic cultures. Dexamethasone (DEX) (10^–9 to 10^–7 M) significantly increased NPY mRNA expression, and the effects were not influenced by coincubation with the sodium channel blocker tetrodotoxin (TTX), indicating that the action of DEX is independent of action potentials. Conversely, insulin (10^–11 to 10^–9 M) significantly inhibited NPY expression stimulated by DEX, and the inhibitory action of insulin was abolished in the presence of TTX. Because GABA and its receptors are expressed in the arcuate nucleus in vivo, we examined whether GABAergic systems were involved in the insulin action. The GABA_B agonist baclofen significantly inhibited NPY expression stimulated by DEX, and the inhibitory action of insulin was completely abolished in the presence of either the GABA_A antagonist bicuculline or the GABA_B antagonist CGP35348 (p-3-aminopropyl-p-diethoxymethyl phosphoric acid). Furthermore, increases in the GABA-synthesizing enzyme glutamic acid decarboxylase 65 (GAD65) mRNA expression preceded decreases in NPY mRNA expression in the arcuate nucleus in the cultures. Experiments in vivo also demonstrated that increases in GAD65 mRNA expression in the arcuate nucleus preceded decreases in the NPY mRNA expression in a fasting-refeeding paradigm and that intracerebroventricular injection of insulin increased GAD65 mRNA expression in the arcuate nucleus in fasted rats. These data suggest that insulin inhibits NPY gene expression in the arcuate nucleus through GABAergic systems.

Key words: neuropeptide Y; arcuate nucleus; glucocorticoid; insulin; GABA; GABA receptors

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Received March 4, 2005; revised August 12, 2005; accepted August 15, 2005.

This article has been cited by other articles:

				H. Shimizu, H. Arima, M. Watanabe, M. Goto, R. Banno, I. Sato, N. Ozaki, H. Nagasaki, and Y. Oiso Glucocorticoids Increase Neuropeptide Y and Agouti-Related Peptide Gene Expression via Adenosine Monophosphate-Activated Protein Kinase Signaling in the Arcuate Nucleus of Rats Endocrinology, September 1, 2008; 149(9): 4544 - 4553. [Abstract] [Full Text] [PDF]

				M. Acosta-Martinez and J. E. Levine Regulation of KATP channel subunit gene expression by hyperglycemia in the mediobasal hypothalamus of female rats Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1801 - E1807. [Abstract] [Full Text] [PDF]

				P. S. Singru, E. Sanchez, C. Fekete, and R. M. Lechan Importance of Melanocortin Signaling in Refeeding-Induced Neuronal Activation and Satiety Endocrinology, February 1, 2007; 148(2): 638 - 646. [Abstract] [Full Text] [PDF]

				M. Goto, H. Arima, M. Watanabe, M. Hayashi, R. Banno, I. Sato, H. Nagasaki, and Y. Oiso Ghrelin Increases Neuropeptide Y and Agouti-Related Peptide Gene Expression in the Arcuate Nucleus in Rat Hypothalamic Organotypic Cultures Endocrinology, November 1, 2006; 147(11): 5102 - 5109. [Abstract] [Full Text] [PDF]

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