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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 5

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Leptin responsiveness maps to a specific region of the hTRH promoter. (a...
Leptin responsiveness maps to a specific region of the hTRH promoter. (a) 293T cells were transfected with a variety of hTRH reporter constructs. Their response to 100 nM leptin was then determined. The data are expressed as relative luciferase activity, and the fold response is indicated above each construct. (b) The promoter sequences of the human, rat, and murine TRH genes are compared in the area of Stat responsiveness. The Stat-responsive element is boldface and located between –141 and –132. The SP-1 site is boldface and underlined and located between –125 and –119. Also shown are the mutations made to create the Statm and ΔSP-1 constructs. (c) 293T cells were transfected with the mTRH reporter construct in an identical paradigm, and its response to leptin was assessed. nTRE, negative thyroid hormone response element.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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