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Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression

Stéphanie Decherf1, Isabelle Seugnet, Soumaya Kouidhi

  • 1Département Régulations, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7221, Evolution des Régulations Endocriniennes, Muséum National d'Histoire Naturelle, Paris, France.

Proceedings of the National Academy of Sciences of the United States of America
|February 18, 2010
PubMed

Insights

Thyroid hormone (T3) negatively regulates the melanocortin 4 receptor (MC4R) gene expression in the hypothalamus. This feedback mechanism is crucial for maintaining energy homeostasis by balancing energy expenditure and intake.

Area of Science:

  • Neuroendocrinology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • The melanocortin 4 receptor (MC4R) is central to leptin signaling, controlling energy balance by influencing food intake and energy expenditure.
  • MC4R is expressed in hypothalamic Thyrotropin-releasing hormone (TRH) neurons, impacting energy usage via TRH and thyroid hormone (T3) production.
  • Mice lacking functional MC4R exhibit obesity, highlighting its critical role in energy homeostasis.

Purpose of the Study:

  • To investigate the hypothesis that T3 exerts negative feedback on MC4R expression to maintain energy homeostasis.
  • To elucidate the molecular mechanisms by which T3 regulates MC4R gene expression in the hypothalamus.

Main Methods:

  • Quantitative PCR and in situ hybridization to assess Mc4r mRNA levels.
  • In silico analysis to identify potential thyroid hormone-response elements (nTREs) in Mc4r regulatory regions.
  • Chromatin immunoprecipitation (ChIP) assays to detect thyroid hormone receptor (TR) binding.
  • Gene reporter assays and mutagenesis to confirm T3-dependent transcriptional regulation.
  • shRNA knockdown, TR over-expression, and mutant mice studies to determine the roles of TRalpha and TRbeta.

Main Results:

  • Hyperthyroidism led to reduced Mc4r mRNA levels in the hypothalamus.
  • Two conserved nTREs were identified in the Mc4r regulatory regions.
  • TRs directly bound to an nTRE in the Mc4r promoter, mediating T3-dependent repression of Mc4r transcription.
  • T3 repressed both Mc4r and Trh transcription in a parallel manner.
  • Both TRalpha and TRbeta were found to contribute to Mc4r regulation.

Conclusions:

  • T3 directly represses Mc4r gene expression in the hypothalamus through TR binding to nTREs.
  • This T3-mediated repression of Mc4r, alongside Trh repression, prevents the stimulatory effects of MC4R on TRH from overriding energy-saving signals.
  • Parallel negative feedback by T3 on hypothalamic Mc4r and Trh is essential for maintaining energy homeostasis.

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