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Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling
Mark Harris, … , Jeffrey S. Flier, Anthony N. Hollenberg
Mark Harris, … , Jeffrey S. Flier, Anthony N. Hollenberg
Published January 1, 2001
Citation Information: J Clin Invest. 2001;107(1):111-120. https://doi.org/10.1172/JCI10741.
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Article

Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling

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Abstract

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, α-melanocyte stimulating hormone (α-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.

Authors

Mark Harris, Carl Aschkenasi, Carol F. Elias, Annie Chandrankunnel, Eduardo A. Nillni, Christian Bjørbæk, Joel K. Elmquist, Jeffrey S. Flier, Anthony N. Hollenberg

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Figure 3

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A near consensus cAMP response element mediates the α-MSH response via C...
A near consensus cAMP response element mediates the α-MSH response via CREB. (a) The cis-acting sequence mediating the response to α-MSH was mapped in 293T cells using the indicated hTRH promoter complexes. (b) A dominant CREB mutant (S133A) or empty vector (PKCR2) was cotransfected in the presence of the –900 TRH reporter construct, and the effects on stimulation were examined after the addition of α-MSH. The data are expressed as fold stimulation. (c) The binding of CREB to Site 4 was assessed using EMSA. Control (NE) or CREB-transfected (C-NE) nuclear extract was incubated with a radiolabeled Site 4 probe. The specificity of CREB binding is demonstrated by its supershift with anti-CREB (αC) antiserum.

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