Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.66398
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Funding
- National Institutes of Health [5R01AT009168, 1S10RR027878]
- OSU Foundation Buhler-Wang Research Fund
- Linus Pauling Institute Marion T. Tsefalas Graduate Fellowship
- Linus Pauling Institute ZRT Laboratory Fund
- OSU School of Biological & Population Health Sciences
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XN and TXN were found to reduce hepatic lipid accumulation in mice, with TXN potentially antagonizing the actions of PPAR gamma. They inhibited cell differentiation by decreasing expression of lipogenesis-related genes.
We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C5761/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated that TXN might antagonize lipogenic PPAR gamma actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A peroxisome proliferator activated receptor gamma (PPAR gamma) competitive binding assay showed that XN and TXN bind to PPAR gamma with an IC50 similar to pioglitazone and 8-10 times stronger than oleate. Molecular docking simulations demonstrated that XN and TXN bind in the PPAR gamma ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPAR gamma.
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