lso known to specifically regulating Mc4r expression in the PVN, with hypothyroidism increasing endogenous Mc4r expression, which parallels the well-established rise in PVN Trh expression also induced by hypothyroidism. We further explored the importance of the thyroid status by studying the concomitant effect of T3 and GW3965 on TR/LXR dialogue. TH replacement in hypothyroid hypothalamus restored the GW3965-dependent repression of the Trh promoter by LXR but not that of Mc4r. These different responses could be explained by a difference in the mechanisms involved, in particular, regarding TR-induced regulations. Data from many in vitro studies on positively regulated genes suggest a model wherein TRs bind to pTREs with or without its ligand, T3. In vivo, the nTREs studied by Decherf et al. in the Mc4r and Trh promoters showed distinct TRb recruitment patterns as a function of T3 presence. Mc4r TRE1 recruited only low levels of TRb in the absence of T3, whereas T3 induced a large increase of TRb binding. In contrast, TRb was found on Trh TRE site 4 without hormone, as previously shown, and T3 induced the dissociation of TRb from Trh TRE site 4. These differences may contribute to the differences BMS-354825 side effects observed on LXR mediated regulations in addition to the different sensitivities to T3-dependent repression of these two genes. In the present study, the in vivo ChIP experiments showed that LXR is recruited to the Trh promoter region in the presence of T3 but not in its absence. In contrast, RXR is recruited to the same region in the absence of T3. We also note that there is no significant simultaneous recruitment of LXR and RXR to the site 4 ofTrh promoter, suggesting that the presence of a NR excludes the other. However, in periphery, LXRs generally function as permissive heterodimer with RXR. But it is worth to note that this heterodimer is observed on LXRE, which is a DR4 whereas we studied LXR binding on the most conserved nTRE identified in Trh, the site 4, a half-site, which could explain the absence of RXR. Furthermore, the Trh site 4 preferentially binds TR/RXR heterodimers. Consequently, we could propose a model where, in hypothyroid mice, TRb would be recruited to the Trh site 4 as a heterodimer with RXR to activate the ligand–independent transcription. After T3 treatment, TRb could dissociate from the site 4 where LXR would be then recruited and represses Trh transcription. It has been reported for Mc4r, that in a hypothyroid state, TRE1 recruited low levels of TRb but T3 treatment induced a large increase of TRb binding. The recruitment of LXR could consequently be inhibited and then, prevent the regulation of Mc4r transcription by LXR, observed in a euthyroid state. These data provide a basis for a model for LXR interference with Trh and Mc4r transcription. Thus, the data show that LXR represses the transcription of T3 regulated genes involved in central control of metabolism in the hypothalamic PVN.