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Coordinate Regulation of Neuropeptide Y and Agouti-Related Peptide Gene Expression by Estrogen Depends on the Ratio of Estrogen Receptor (ER) to ERß in Clonal Hypothalamic Neurons

Departments of Physiology (D.T., F.C., D.D.B.), Obstetrics and Gynaecology (D.D.B.), and Medicine (D.D.B.), University of Toronto and Division of Cellular and Molecular Biology (D.D.B.), Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada M5S 1A8

Address all correspondence and requests for reprints to: Denise D. Belsham, Ph.D., Department of Physiology, University of Toronto, Medical Sciences Building 3247A, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: d.belsham{at}utoronto.ca.

Neuropeptide Y (NPY) and agouti-related peptide (AgRP) stimulate feeding, whereas NPY also facilitates the estrogen-mediated preovulatory GnRH surge. In addition to regulating reproductive function, estrogen also acts as an anorexigenic hormone, although it is not yet known which hypothalamic neurons are involved in this process. We hypothesize that estrogen may directly control hypothalamic NPY and/or AgRP synthesis to influence energy homeostasis. Using two clonal, murine hypothalamic neuronal cell models, N-38 and N-42, we demonstrate that 17ß-estradiol differentially regulates estrogen receptor (ER) and ERß levels, as well as NPY and AgRP gene expression in a manner that is temporally coordinated with the changes in ER abundance. The estrogen-mediated repression of NPY and AgRP mRNA levels in N-38 and N-42 neurons require either ER and ERß or ER alone, respectively, whereas the induction of NPY and AgRP in N-38 neurons is strictly ERß dependent, as assessed by ER-specific agonists and small interfering RNA knockdown of ER or ERß. Through transient transfection analysis in N-38 neurons, we have mapped the estrogen-mediated repression of NPY to within –1078 of the 5' regulatory region of the NPY gene. Our results provide the first evidence that NPY and AgRP gene expression is directly regulated by estrogen in specific hypothalamic neurons, and that this regulation is dependent upon the ratio of ERß to ER. The biphasic control of neuronal NPY/AgRP transcription may be a mechanism by which estrogen has distinct effects on both energy homeostasis and reproduction.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol

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