Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling.
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, alpha-melanocyte stimulating hormone (alpha-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.
Harris
M
M
Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Aschkenasi
C
C
Elias
C F
CF
Chandrankunnel
A
A
Nillni
E A
EA
Bjøorbaek
C
C
Elmquist
J K
JK
Flier
J S
JS
Hollenberg
A N
AN
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D004247:DNA / Q000235:genetics; D005215:Fasting / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4; D054411:Receptors, Leptin; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics*; D014157:Transcription Factors; D000521:alpha-MSH / Q000378:metabolism / Q000494:pharmacology
C515448:LEPR protein, human; D020738:Leptin; D011506:Proteins; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; D054411:Receptors, Leptin; D018000:Receptors, Peptide; D012097:Repressor Proteins; C106644:SOCS3 protein, human; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D000521:alpha-MSH; D013973:Thyrotropin-Releasing Hormone; D004247:DNA