Abstract
Reversing the escalating rate of obesity requires increased knowledge of the molecular mechanisms controlling energy balance. Liver X receptors (LXRs) and thyroid hormone receptors (TRs) are key physiological regulators of energetic metabolism. Analysing interactions between these receptors in the periphery has led to a better understanding of the mechanisms involved in metabolic diseases. However, no data is available on such interactions in the brain. We tested the hypothesis that hypothalamic LXR/TR interactions could co-regulate signalling pathways involved in the central regulation of metabolism. Using in vivo gene transfer we show that LXR activation by its synthetic agonist GW3965 represses the transcriptional activity of two key metabolic genes, Thyrotropin-releasing hormone (Trh) and Melanocortin receptor type 4 (Mc4r) in the hypothalamus of euthyroid mice. Interestingly, this repression did not occur in hypothyroid mice but was restored in the case of Trh by thyroid hormone (TH) treatment, highlighting the role of the triiodothyronine (T3) and TRs in this dialogue. Using shLXR to knock-down LXRs in vivo in euthyroid newborn mice, not only abrogated Trh repression but actually increased Trh transcription, revealing a potential inhibitory effect of LXR on the Hypothalamic-Pituitary-Thyroid axis. In vivo chromatin immunoprecipitation (ChIP) revealed LXR to be present on the Trh promoter region in the presence of T3 and that Retinoid X Receptor (RXR), a heterodimerization partner for both TR and LXR, was never recruited simultaneously with LXR. Interactions between the TR and LXR pathways were confirmed by qPCR experiments. T3 treatment of newborn mice induced hypothalamic expression of certain key LXR target genes implicated in metabolism and inflammation. Taken together the results indicate that the crosstalk between LXR and TR signalling in the hypothalamus centres on metabolic and inflammatory pathways.
Highlights
Obesity contributes to the aetiology of common associated metabolic diseases [1,2,3]
The need for a detailed study on the involvement of Liver X receptors (LXRs) in central metabolic pathways and control of energy homeostasis is underlined by the fact that it has recently been shown that the central melanocortin pathway, 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 [14]
Crosstalks between pathways regulated by these two nuclear receptors (NR) have been reported, especially regarding lipid metabolism-related genes [8] and in other physiological systems such as the central nervous system [23] as LXRs are expressed in, notably, the brain stem, the hypothalamus and the cortex [24]. 24-(S)-hydroxycholesterol-liganded LXR regulates cholesterol availability in the brain playing an important role in hypothalamic cholesterol homeostasis, which is crucial for brain physiology [25]
Summary
Obesity contributes to the aetiology of common associated metabolic diseases [1,2,3]. 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 recently been shown that the central melanocortin pathway, 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 [14]. These results lead to the hypothesis that LXR signalling, in the hypothalamus, may interact with this pathway
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