文章基本信息

标题：Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression
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作者：Stéphanie Decherf ; Isabelle Seugnet ; Soumaya Kouidhi 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：9
页码：4471-4476
DOI：10.1073/pnas.0905190107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The type 4 melanocortin receptor MC4R, a key relay in leptin signaling, links central energy control to peripheral reserve status. MC4R activation in different brain areas reduces food intake and increases energy expenditure. Mice lacking Mc4r are obese. Mc4r is expressed by hypothalamic paraventricular Thyrotropin-releasing hormone (TRH) neurons and increases energy usage through activation of Trh and production of the thyroid hormone tri-iodothyronine (T3). These facts led us to test the hypothesis that energy homeostasis should require negative feedback by T3 on Mc4r expression. Quantitative PCR and in situ hybridization showed hyperthyroidism reduces Mc4r mRNA levels in the paraventricular nucleus. Comparative in silico analysis of Mc4r regulatory regions revealed two evolutionarily conserved potential negative thyroid hormone-response elements (nTREs). In vivo ChIP assays on mouse hypothalamus demonstrated association of thyroid hormone receptors (TRs) with a region spanning one nTRE. Further, in vivo gene reporter assays revealed dose-dependent T3 repression of transcription from the Mc4r promoter in mouse hypothalamus, in parallel with T3-dependent Trh repression. Mutagenesis of the nTREs in the Mc4r promoter demonstrated direct regulation by T3, consolidating the ChIP results. In vivo shRNA knockdown, TR over-expression approaches and use of mutant mice lacking specific TRs showed that both TR and TR{beta} contribute to Mc4r regulation. T3 repression of Mc4r transcription ensures that the energy-saving effects of T3 feedback on Trh are not overridden by MC4R activation of Trh. Thus parallel repression by T3 on hypothalamic Mc4r and Trh contributes to energy homeostasis.
关键词：energy homeostasis ; gene transcription ; leptin pathway ; ligand-dependent repression ; thyrotropin-releasing hormone