Oral Presentation The International Congress of Neuroendocrinology 2014

Integrating TH signalling in hypothalamic control of metabolism  (#94)

Marie-Stéphanie Clerget-Froidevaux 1 , Stéphanie Decherf 1 , Rym Ghaddab-Zroud 1 , Soumaya Kouidhi 1 2 , Isabelle Seugnet 1 , Barbara A Demeneix 1
  1. CNRS UMR7221. National Museum of Natural History, Paris, France
  2. Faculty of Sciences, University of Manar I, , Tunis, Tunisia

The global obesity pandemic is a major cause of increasing healthcare costs, obesity being often associated with diabetes or atherosclerosis. Such statistics emphasize the need to better understand the physiology of balancing energy intake and energy expenditure. Obesity etiology is multi-factorial, implicating environmental, physiological and genetic causes. Major players are the central control mechanisms relaying the hunger and satiety cascades, that have their neuronal and gene networks relayed across different hypothalamic nuclei. One key endocrine factor governing both sides of the intake/expenditure equation is thyroid hormone (TH). This hormone acts through receptors (TRs, thyroid receptors) members of the Nuclear Receptor (NR) superfamily. This family includes other metabolically linked NRs notably LXR (liver X receptors) and PPARs (peroxisome-proliferator-activated receptors). Multiple cross-talk between NRs modulate energy homeostasis in the periphery. Over the past few years, our team has been working on decrypting these interactions at the level of the hypothalamus.

First, we studied the interactions between TH and another key pathway implicated in food intake and energy expenditure regulation, the αMSH pathway. An important finding was that TH directly regulates Mc4r expression in major brain areas relevant to metabolic homeostasis, including the Trh neuron1. This result reinforces the concept of the major role of TH and the TRH neuron in central integration of endocrine and metabolic signaling and energy homeostasis. Working on TH regulation of Trh transcription, we demonstrated that both PPARγ2 and LXRs modulated this regulation, both NRs inhibiting Trh transcription. We also demonstrated that competition for RXR, which is a common heterodimerization partner for TR3, LXR4 and PPAR, could represent one of the mechanisms underlying this hypothalamic crosstalk.

Taken together, our results shed light on the importance of crosstalk between different classes of hypothalamic NR in controlling energy homeostasis.
  1. Decherf S, Seugnet I, Kouidhi S, Lopez-Juarez A, Clerget-Froidevaux M-S, B.A. Demeneix (2010) Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression. Proceedings of the National Academy of Sciences of the United States of America 107: 4471-4476.
  2. Kouidhi S, Seugnet I, Decherf S, Guissouma H, Elgaaied AB, Demeneix B. and Clerget-Froidevaux MS. (2010) Peroxisome proliferator526 activated receptor-gamma (PPARgamma) modulates hypothalamic Trh regulation in vivo. Mol Cell Endocrinol 317: 44-52.
  3. Decherf S, Seugnet I, Becker N, Demeneix BA, Clerget-Froidevaux MS (2013) Retinoic X receptor subtypes exert differential effects on the regulation of Trh transcription. Mol Cell Endocrinol 381:115-123.
  4. Ghaddab-Zroud R., Seugnet I., Steffensen KR., Demeneix B.A., Clerget-Froidevaux MS. Liver X receptor regulation of thyrotropin-releasing hormone transcription in mouse hypothalamus is dependent on thyroid status. Plos One (revision)