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The Journal of Neuroscience, October 12, 2005, 25(41):9497-9506; doi:10.1523/JNEUROSCI.2269-05.2005

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Cellular/Molecular
Anorexigenic Hormones Leptin, Insulin, and -Melanocyte-Stimulating Hormone Directly Induce Neurotensin (NT) Gene Expression in Novel NT-Expressing Cell Models

Hong Cui,¹ Fang Cai,¹ and Denise D. Belsham^1,2

¹Department of Physiology, University of Toronto, and ²Departments of Obstetrics and Gynecology and Medicine, University of Toronto, and Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada M5S 1A8

Neurotensin (NT) is implicated in the regulation of energy homeostasis, in addition to its many described physiological functions. NT is postulated to mediate, in part, the effects of leptin in the hypothalamus. We generated clonal, immortalized hypothalamic cell lines, N-39 and N-36/1, which are the first representative NT-expressing cell models available for the investigation of NT gene regulation and control mechanisms. The cell lines express the Ob-R_b leptin receptor neuropeptide Y (NPY)-Y1, Y2, Y4, Y5 receptors, melanocortin 4 receptor, insulin receptor, and the NT receptor. NT mRNA levels are induced by 1.5-fold to twofold with leptin, insulin, and -melanocyte stimulating hormone treatments but not by NPY. Leptin-mediated induction of NT gene expression was biphasic at 10^-11 and 10^-7 M. The leptin responsive region was localized to within -381 to -250 bp of the 5' regulatory region of the NT gene. Furthermore, we demonstrated direct leptin-mediated signal transducers and activators of transcription (STAT) binding to this region at 10^-11 M, but not 10^-7 M leptin, in chromatin precipitation assays. Leptin-induced NT regulation was attenuated by dominant-negative STAT3 protein expression. These data support the hypothesis that NT may have a direct role in the neuroendocrine control of feeding and energy homeostasis.

Key words: neurotensin; hypothalamic neurons; leptin; -MSH; insulin; transcription

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Received June 3, 2005; revised August 19, 2005; accepted August 26, 2005.

This article has been cited by other articles:

				D. Titolo, C. M. Mayer, S. S. Dhillon, F. Cai, and D. D. Belsham Estrogen Facilitates both Phosphatidylinositol 3-Kinase/Akt and ERK1/2 Mitogen-Activated Protein Kinase Membrane Signaling Required for Long-Term Neuropeptide Y Transcriptional Regulation in Clonal, Immortalized Neurons J. Neurosci., June 18, 2008; 28(25): 6473 - 6482. [Abstract] [Full Text] [PDF]

				F. Cai, A. V Gyulkhandanyan, M. B Wheeler, and D. D Belsham Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin J. Endocrinol., March 1, 2007; 192(3): 605 - 614. [Abstract] [Full Text] [PDF]

				H. Cui, F. Cai, and D. D. Belsham Leptin signaling in neurotensin neurons involves STAT, MAP kinases ERK1/2, and p38 through c-Fos and ATF1 FASEB J, December 1, 2006; 20(14): 2654 - 2656. [Abstract] [Full Text] [PDF]

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