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.