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

Starvation causes a rapid reduction in thyroid hormone levels in rodents. T his adaptive response is caused by a reduction in thyrotropin-releasing hor mone (TRH) expression that can be reversed by the administration of leptin. Here we examined hypothalamic signaling pathways engaged by leptin to upre gulate TRH gene expression. As assessed by leptin-induced expression of sup pressor of cytokine signaling-3 (SOCS-3) in fasted rats, TRH neurons in the paraventricular nucleus are activated directly by leptin. To a greater deg ree, they also contain melanocortin-4 receptors (MC4Rs), implying that lept in 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 ph osphorylation and DNA binding of the cAMP response element binding protein (CREB), and leptin signaling directly regulates the TRH promoter through th e phosphorylation of signal transducer and activator of transcription 3 (St at3). Indeed, a novel Stat-response element in the TRH promoter is necessar y for leptin's effect. Thus, the TRH promoter is an ideal target for furthe r characterizing the integration of transcriptional pathways through which leptin acts.