Liver X Receptor Is a Transcriptional Repressor of the Uncoupling Protein 1 Gene and the Brown Fat Phenotype

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Molecular and Cellular Biology (Impact Factor: 4.78). 05/2008; 28(7):2187-200. DOI: 10.1128/MCB.01479-07
Source: PubMed


The adipocyte integrates crucial information about metabolic needs in order to balance energy intake, storage, and expenditure.
Whereas white adipose tissue stores energy, brown adipose tissue is a major site of energy dissipation through adaptive thermogenesis
mediated by uncoupling protein 1 (UCP1) in mammals. In both white and brown adipose tissue, nuclear receptors and their coregulators,
such as peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivator 1α (PGC-1α), play key roles in regulating
their development and metabolic functions. Here we show the unexpected role of liver X receptor α (LXRα) as a direct transcriptional
inhibitor of β-adrenergic receptor-mediated, cyclic AMP-dependent Ucp1 gene expression through its binding to the critical enhancer region of the Ucp1 promoter. The mechanism of inhibition involves the differential recruitment of the corepressor RIP140 to an LXRα binding
site that overlaps with the PPARγ/PGC-1α response element, resulting in the dismissal of PPARγ. The ability of LXRα to dampen
energy expenditure in this way provides another mechanism for maintaining a balance between energy storage and utilization.

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    • "The phosphorylation of CREB by adrenergic stimulation induces the robust expression of thermogenic genes in BAT, including Ucp1 and Pgc1a. Conversely, several nuclear hormone receptors and corepressors such as LXRa and RIP140 negatively regulate thermogenic genes (Leonardsson et al., 2004; Wang et al., 2008). LXRa selectively represses Ucp1 induction by binding adjacent to CREB on the Ucp1 promoter. "
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    ABSTRACT: To understand the contribution of adipose tissue fatty acid oxidation to whole-body metabolism, we generated mice with an adipose-specific knockout of carnitine palmitoyltransferase 2 (CPT2(A-/-)), an obligate step in mitochondrial long-chain fatty acid oxidation. CPT2(A-/-) mice became hypothermic after an acute cold challenge, and CPT2(A-/-) brown adipose tissue (BAT) failed to upregulate thermogenic genes in response to agonist-induced stimulation. The adipose-specific loss of CPT2 resulted in diet-dependent changes in adiposity but did not result in changes in body weight on low- or high-fat diets. Additionally, CPT2(A-/-) mice had suppressed high-fat diet-induced oxidative stress and inflammation in visceral white adipose tissue (WAT); however, high-fat diet-induced glucose intolerance was not improved. These data show that fatty acid oxidation is required for cold-induced thermogenesis in BAT and high-fat diet-induced oxidative stress and inflammation in WAT. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Preview · Article · Jan 2015 · Cell Reports
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    • "This pathway oxidizes lipids and dissipates heat energy as a result of the uncoupling of the mitochondrial electron transport chain due to ATP production by uncoupling protein 1 (UCP1). Thermogenesis is elevated in the mitochondria-rich BAT, and it is also observed in WAT, which contains brown-like cells [9] [10]. "
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    ABSTRACT: The present study aimed to investigate whether olive leaf extract (OLE) prevents high-fat diet (HFD)-induced obesity in mice and to explore the underlying mechanisms. Mice were randomly divided into groups that received a chow diet (CD), HFD, or 0.15% OLE-supplemented diet (OLD) for 8 weeks. OLD-fed mice showed significantly reduced body weight gain, visceral fat-pad weights, and plasma lipid levels as compared with HFD-fed mice. OLE significantly reversed the HFD-induced upregulation of WNT10b- and galanin-mediated signaling molecules and key adipogenic genes (PPAR γ , C/EBP α , CD36, FAS, and leptin) in the epididymal adipose tissue of HFD-fed mice. Furthermore, the HFD-induced downregulation of thermogenic genes involved in uncoupled respiration (SIRT1, PGC1 α , and UCP1) and mitochondrial biogenesis (TFAM, NRF-1, and COX2) was also significantly reversed by OLE. These results suggest that OLE exerts beneficial effects against obesity by regulating the expression of genes involved in adipogenesis and thermogenesis in the visceral adipose tissue of HFD-fed mice.
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    • "Adaptive thermogenesis in small mammals mostly takes place in BAT through the specific activity of UCP1 (7;8. Recently, Sheila Collins and her group reported that LXRα is a transcriptional repressor of UCP1 21. Therefore, we investigated whether rhein enhances the expression of UCP1 to increase adaptive thermogenesis to counteract obesity. "
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    ABSTRACT: Liver X receptors (LXRs) play important roles in regulating cholesterol homeostasis, and lipid and energy metabolism. Therefore, LXR ligands could be used for the management of metabolic disorders. We evaluated rhein, a natural compound from Rheum palmatum L., as an antagonist for LXRs and investigated its anti-obesity mechanism in high-fat diet-fed mice. Surface plasmon resonance assays were performed to examine the direct binding of rhein to LXRs. LXR target gene expression was assessed in 3T3-L1 adipocytes and HepG2 hepatic cells in vitro. C57BL/6J mice fed a high-fat diet were orally administered with rhein for 4 weeks, and then the expression levels of LXR-related genes were analyzed. Rhein bound directly to LXRs. The expression levels of LXR target genes were suppressed by rhein in 3T3-L1 and HepG2 cells. In white adipose tissue, muscle and liver, rhein reprogrammed the expression of LXR target genes related to adipogenesis and cholesterol metabolism. Rhein activated uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) in wild-type mice, but did not affect UCP1 expression in LXR knockout mice. In HIB-1B brown adipocytes, rhein activated the UCP1 gene by antagonizing the repressive effect of LXR on UCP1 expression. This study suggests that rhein may protect against obesity and related metabolic disorders through LXR antagonism and regulation of UCP1 expression in BAT.
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