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Regulation of thyrotropin-releasing hormone-expressing neurons in paraventricular nucleus of the hypothalamus by signals of adiposity.

ABSTRACT: Fasting-induced suppression of thyroid hormone levels is an adaptive response to reduce energy expenditure in both humans and mice. This suppression is mediated by the hypothalamic-pituitary-thyroid axis through a reduction in TRH levels expressed in neurons of the paraventricular nucleus of the hypothalamus (PVN). TRH gene expression is positively regulated by leptin. Whereas decreased leptin levels during fasting lead to a reduction in TRH gene expression, the mechanisms underlying this process are still unclear. Indeed, evidence exists that TRH neurons in the PVN are targeted by leptin indirectly via the arcuate nucleus, whereas correlative evidence for a direct action exists as well. Here we provide both in vivo and in vitro evidence that the activity of hypothalamic-pituitary-thyroid axis is regulated by both direct and indirect leptin regulation. We show that both leptin and ?-MSH induce significant neuronal activity mediated through a postsynaptic mechanism in TRH-expressing neurons of PVN. Furthermore, we provide in vivo evidence indicating the contribution of each pathway in maintaining serum levels of thyroid hormone.

SUBMITTER: Ghamari-Langroudi M

PROVIDER: S-EPMC2999480 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Regulation of thyrotropin-releasing hormone-expressing neurons in paraventricular nucleus of the hypothalamus by signals of adiposity.

Ghamari-Langroudi Masoud M Vella Kristen R KR Srisai Dollada D Sugrue Michelle L ML Hollenberg Anthony N AN Cone Roger D RD

Molecular endocrinology (Baltimore, Md.) 20101013 12

Fasting-induced suppression of thyroid hormone levels is an adaptive response to reduce energy expenditure in both humans and mice. This suppression is mediated by the hypothalamic-pituitary-thyroid axis through a reduction in TRH levels expressed in neurons of the paraventricular nucleus of the hypothalamus (PVN). TRH gene expression is positively regulated by leptin. Whereas decreased leptin levels during fasting lead to a reduction in TRH gene expression, the mechanisms underlying this proces ...[more]

PMID: 20943814

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Project description:Thyroid hormone (T3) inhibits thyrotropin-releasing hormone (TRH) synthesis in the hypothalamic paraventricular nucleus (PVN). Although the T3 receptor (TR) β2 is known to mediate the negative regulation of the prepro-TRH gene, its molecular mechanism remains unknown. Our previous studies on the T3-dependent negative regulation of the thyrotropin β subunit (TSHβ) gene suggest that there is a tethering mechanism, whereby liganded TRβ2 interferes with the function of the transcription factor, GATA2, a critical activator of the TSHβ gene. Interestingly, the transcription factors Sim1 and Arnt2, the determinants of PVN differentiation in the hypothalamus, are reported to induce expression of TRβ2 and GATA2 in cultured neuronal cells. Here, we confirmed the expression of the GATA2 protein in the TRH neuron of the rat PVN using immunohistochemistry with an anti-GATA2 antibody. According to an experimental study from transgenic mice, a region of the rat prepro-TRH promoter from nt. -547 to nt. +84 was able to mediate its expression in the PVN. We constructed a chloramphenicol acetyltransferase (CAT) reporter gene containing this promoter sequence (rTRH(547)-CAT) and showed that GATA2 activated the promoter in monkey kidney-derived CV1 cells. Deletion and mutation analyses identified a functional GATA-responsive element (GATA-RE) between nt. -357 and nt. -352. When TRβ2 was co-expressed, T3 reduced GATA2-dependent promoter activity to approximately 30%. Unexpectedly, T3-dependent negative regulation was maintained after mutation of the reported negative T3-responsive element, site 4. T3 also inhibited the GATA2-dependent transcription enhanced by cAMP agonist, 8-bromo-cAMP. A rat thyroid medullary carcinoma cell line, CA77, is known to express the preproTRH mRNA. Using a chromatin immunoprecipitation assay with this cell line where GATA2 expression plasmid was transfected, we observed the recognition of the GATA-RE by GATA2. We also confirmed GATA2 binding using gel shift assay with the probe for the GATA-RE. In CA77 cells, the activity of rTRH(547)-CAT was potentiated by overexpression of GATA2, and it was inhibited in a T3-dependent manner. These results suggest that GATA2 transactivates the rat prepro-TRH gene and that liganded TRβ2 interferes with this activation via a tethering mechanism as in the case of the TSHβ gene.

Dataset Information

Regulation of thyrotropin-releasing hormone-expressing neurons in paraventricular nucleus of the hypothalamus by signals of adiposity.

Publications

Regulation of thyrotropin-releasing hormone-expressing neurons in paraventricular nucleus of the hypothalamus by signals of adiposity.

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