In the periphery, regulation of energetic metabolism involves several types of nuclear receptors. Among NRs, LXRs, activated by cholesterol metabolites, are known to be key regulators of lipid and cholesterol metabolism. The two related LXRs, LXRa and LXRb are part of the emerging significant newer drug targets within the NR family. A second type of NR, TRs, plays a major role in controlling energy metabolism. THs are known to regulate, at a transcriptional level, all the steps of cholesterol metabolism, and TRb1 is the main receptor isoform involved. Given the role played by these NR in metabolism, dysregulations of metabolic functions controlled by LXR/TRs can alter the homeostatic control circuits, contributing to the pathogenesis of many common metabolic diseases, such as obesity, insulin resistance, type 2 diabetes, hyperlipidaemia, atherosclerosis, and gallbladder disease. Interactions between LXR and TR have been described in the periphery. These interactions are based on two major points: First, LXRs and TRs both use retinoid X receptors as common heterodimerization partner, a fact that can engender competition for RXR if quantities are limiting. Second, the consensus response elements for LXRs and TRs are very similar. However, so far no data are available on how such interactions affect regulations at the central level, whereas, it is well known that hypothalamus is considered as the central integrator of metabolic regulation. Consequently, the key players are the central controls of food intake, relayed by neural and gene networks in different hypothalamic nuclei. Indeed, in the context of thyroid hormone – induced gene regulation, our group has focused on hypothalamic interactions between different signalling pathways controlling metabolism. In particular, we showed that TH, through TRs, is directly involved in transcriptional regulation of melanocortin receptor type 4. Moreover, the need for a detailed study on the involvement of LXR in central metabolic pathways and control of energy homeostasis is underlined by the fact that it has Ibrutinib recently been shown that the central melanocortin pathway, particularly hypothalamic MC4R is involved in the control of hepatic cholesterol metabolism: in addition to facilitating hepatic cholesterol synthesis, the central melanocortin system influences cholesterol transport by modulating HDL cholesterol levels. These results lead to the hypothesis that LXR signalling, in the hypothalamus, may interact with this pathway. In the current study, we analysed, at the hypothalamic level, how LXR may interfere with transcriptional regulation induced by TRs. Using in vivo gene transfer we show that activation of LXR by its synthetic agonist GW3965 represses the transcriptional activity of two known TH target genes involved in the central control of metabolism, Trh and Mc4r promoters, and this only in euthyroid mice. This repression was restored by TH treatment in hypothyroid mice.