Converging pathways regulate energy metabolism

The satiety factor leptin is produced by body fat and acts in the brain to modulate feeding behavior and energy expenditure. Harris et al. have examined the transcriptional regulation of TRH, a leptin-sensitive gene whose product, thyrotropin-releasing hormone, ultimately regulates thyroid hormone levels. They argue here that two distinct leptin-dependent signaling pathways activate the TRH promoter in the paraventricular nucleus of the hypothalamus (PVH). Leptin was already known to act in the neighboring arcuate nucleus to induce the expression of a-melanocyte stimulating hormone (a-MSH), which acts on the cells of the PVN. In addition, the authors also show that PVH neurons express the leptin receptor and certain downstream signaling molecules that could allow for direct induction of TRH by leptin. Working in heterologous cells, Harris et al. have reconstructed the signaling pathways that lead to TRH induction, and they show that both direct leptin effects and a-MSH–mediated effects converge on the TRH promoter. Leptin- and a-MSH–dependent signals act at distinct promoter elements, which can be mutated to block either the direct or the indirect pathway. The authors also show that thyroid hormone can suppress the production of TRH, at least in cultured cells, establishing yet another class of stimulus that might act on the TRH promoter, which must integrate the various signals to modulate energy metabolism.