Rhein protects against obesity and related metabolic disorders through liver X receptor-mediated uncoupling protein 1 upregulation in brown adipose tissue

• Published in: International journal of biological sciences Vol. 8; no. 10; pp. 1375 - 1384
• Main Authors: Sheng, Xiaoyan, Zhu, Xuehua, Zhang, Yuebo, Cui, Guoliang, Peng, Linling, Lu, Xiong, Zang, Ying Qin
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2012
• Subjects: Adipocytes - metabolism; Adipose Tissue, Brown - drug effects; Adipose Tissue, Brown - metabolism; Administration, Oral; Animals; Anthraquinones - chemistry; Anthraquinones - pharmacology; Anthraquinones - therapeutic use; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - pharmacology; Anti-Obesity Agents - therapeutic use; Diet, High-Fat; Gene Expression - drug effects; Gene Knockout Techniques; Ion Channels - genetics; Ion Channels - metabolism; Liver X Receptors; Metabolic Diseases - drug therapy; Metabolic Diseases - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular Sequence Data; NIH 3T3 Cells; Obesity - drug therapy; Obesity - metabolism; Orphan Nuclear Receptors - antagonists & inhibitors; Orphan Nuclear Receptors - genetics; Research Paper; Rheum - chemistry; Surface Plasmon Resonance; Uncoupling Protein 1; UCP1; rhein; antagonist; diet-induced obesity; LXR
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.4575

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.