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

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

Research output: Contribution to journalArticle

242 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)111-120
Number of pages10
JournalJournal of Clinical Investigation
Volume107
Issue number1
StatePublished - 2001

Fingerprint

Melanocortins
Thyrotropin-Releasing Hormone
Leptin
Genes
Receptor, Melanocortin, Type 4
Phosphorylation
Melanocyte-Stimulating Hormones
Cyclic AMP Response Element-Binding Protein
STAT3 Transcription Factor
Paraventricular Hypothalamic Nucleus
Response Elements
Starvation
Thyroid Hormones
Rodentia
Up-Regulation
Cytokines
Ligands
Gene Expression
Neurons

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Harris, M., Aschkenasi, C., Elias, C. F., Chandrankunnel, A., Nillni, E. A., Bjørbæk, C., ... Hollenberg, A. N. (2001). Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. Journal of Clinical Investigation, 107(1), 111-120.

Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. / Harris, Mark; Aschkenasi, Carl; Elias, Carol F.; Chandrankunnel, Annie; Nillni, Eduardo A.; Bjørbæk, Christian; Elmquist, Joel K.; Flier, Jeffrey S.; Hollenberg, Anthony N.

In: Journal of Clinical Investigation, Vol. 107, No. 1, 2001, p. 111-120.

Research output: Contribution to journalArticle

Harris, M, Aschkenasi, C, Elias, CF, Chandrankunnel, A, Nillni, EA, Bjørbæk, C, Elmquist, JK, Flier, JS & Hollenberg, AN 2001, 'Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling', Journal of Clinical Investigation, vol. 107, no. 1, pp. 111-120.
Harris M, Aschkenasi C, Elias CF, Chandrankunnel A, Nillni EA, Bjørbæk C et al. Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. Journal of Clinical Investigation. 2001;107(1):111-120.
Harris, Mark ; Aschkenasi, Carl ; Elias, Carol F. ; Chandrankunnel, Annie ; Nillni, Eduardo A. ; Bjørbæk, Christian ; Elmquist, Joel K. ; Flier, Jeffrey S. ; Hollenberg, Anthony N. / Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. In: Journal of Clinical Investigation. 2001 ; Vol. 107, No. 1. pp. 111-120.
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