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

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 4

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T3 blocks α-MSH–mediated upregulation of the hTRH promoter. (a) 293T cel...
T3 blocks α-MSH–mediated upregulation of the hTRH promoter. (a) 293T cells were cotransfected with expression vectors for the TRβ isoforms. The cells were incubated with either 100 nM α-MSH alone or with α-MSH and 100 nM T3. The data are expressed as fold stimulation from untreated cells. (b) EMSA was performed with radiolabeled Site 4 and CREB-transfected nuclear extract in the presence or absence of in vitro translated hTRβ2. (c) GST-TRβ1 or GST-TRβ2 was incubated with radiolabeled SRC-1 or CREB either in the presence or absence of 1 μM T3. Lane 9, CREB (C) input. Lane 10, SRC-1 (S) input.