Scott,
Your work sound very complicated, but interesting as well. Good luck.
New on leptin mechanism;
J Clin Invest, January 2001, Volume 107, Number 1, 111-120
Copyright ©2001 by the American Society for Clinical Investigation
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Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling
Mark Harris1, Carl Aschkenasi1, Carol F. Elias1, Annie Chandrankunnel1, Eduardo A. Nillni2, Christian Bjørbæk1, Joel K. Elmquist1,3, Jeffrey S. Flier1 and Anthony N. Hollenberg1
1 Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA 2 Division of Endocrinology, Rhode Island Hospital and Brown University School of Medicine, Providence, Rhode Island, USA 3 Department of Neurology, Beth Israel Deaconess Medical Center and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA
Address correspondence to: Anthony N. Hollenberg, Division of Endocrinology, Beth Israel Deaconess Medical Center-Research North, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-2151; Fax: (617) 667-2927; E-mail: thollenb@caregroup.harvard.edu.
Received for publication July 11, 2000, and accepted in revised form November 21, 2000.
Starvation causes a rapid reduction in thyroid hormone levels in rodents. This adaptive response is caused by a reduction in thyrotropin-releasing hormone (TRH) expression that can be reversed by the administration of leptin. Here we examined hypothalamic signaling pathways engaged by leptin to upregulate TRH gene expression. As assessed by leptin-induced expression of suppressor of cytokine signaling–3 (SOCS-3) in fasted rats, TRH neurons in the paraventricular nucleus are activated directly by leptin. To a greater degree, they also contain melanocortin-4 receptors (MC4Rs), implying that leptin can act directly or indirectly by increasing the production of the MC4R ligand, -melanocyte stimulating hormone (-MSH), to regulate TRH expression. We further demonstrate that both pathways converge on the TRH promoter. The melanocortin system activates the TRH promoter through the phosphorylation and DNA binding of the cAMP response element binding protein (CREB), and leptin signaling directly regulates the TRH promoter through the phosphorylation of signal transducer and activator of transcription 3 (Stat3). Indeed, a novel Stat-response element in the TRH promoter is necessary for leptin’s effect. Thus, the TRH promoter is an ideal target for further characterizing the integration of transcriptional pathways through which leptin acts. |
