Effect of xanthohumol and isoxanthohumol on 3T3-L1 cell apoptosis and adipogenesis

Department of Animal and Dairy Science, 444 Edgar L. Rhodes Center for Animal and Dairy Science, University of Georgia, Athens, GA 30602-2771, USA.
APOPTOSIS (Impact Factor: 3.69). 12/2007; 12(11):1953-63. DOI: 10.1007/s10495-007-0130-4
Source: PubMed


Xanthohumol (XN), the chalcone from beer hops has several biological activities. XN has been shown to induce apoptosis in cancer cells and also has been reported to be involved in lipid metabolism. Based on these studies and our previous work with natural compounds, we hypothesized that XN and its isomeric flavanone, isoxanthohumol (IXN), would induce apoptosis in adipocytes through the mitochondrial pathway and would inhibit maturation of preadipocytes. Adipocytes were treated with various concentrations of XN or IXN. In mature adipocytes both XN and IXN decreased viability, increased apoptosis and increased ROS production, XN being more effective. Furthermore, the antioxidants ascorbic acid and 2-mercaptoethanol prevented XN and IXN-induced ROS generation and apoptosis. Immunoblotting analysis showed an increase in the levels of cytoplasmic cytochrome c and cleaved poly (ADP-ribose) polymerase (PARP) by XN and IXN. Concomitantly, we observed activation of the effectors caspase-3/7. In maturing preadipocytes both XN and IXN were effective in reducing lipid content, XN being more potent. Moreover, the major adipocyte marker proteins such as PPARgamma, C/EBPalpha, and aP2 decreased after treatment with XN during the maturation period and that of DGAT1 decreased after treatment with XN and IXN. Taken together, our data indicate that both XN and IXN inhibit differentiation of preadipocytes, and induce apoptosis in mature adipocytes, but XN is more potent.

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    • "angustifolia. Several studies reported that some flavonoids and phenolic compounds are able to inhibit adipogenesis of 3T3-L1 preadipocytes by inhibiting mitotic clonal expansion, triglyceride accumulation, and PPARγ expression (Harmon and Harp, 2001; Choi et al., 2006; Yang et al., 2006; 2007). Quercetin, a flavonoid, has been shown to be involved in preventing insulin receptor tyrosine kinase from phosphorylating substrate, hence blocking insulinmediated lipogenesis (Harmon and Harp, 2001). "
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    ABSTRACT: Objective: This study examined the anti-adipogenic effects of extracts of Ficus deltoidea var. deltoidia and var. angustifolia, a natural slimming aid, on 3T3-L1 adipocytes. Methods: Methanol and water extracts of leaves of the F. deltoidea varieties were analyzed to determine their total flavonoid content (TFC) and total phenolic content (TPC), respectively. The study was initiated by determining the maximum non-toxic dose (MNTD) of the methanol and water extracts for 3T3-L1 preadipocytes. Possible anti-adipogenic effects were then examined by treating 2-d post confluent 3T3-L1 preadipocytes with either methanol extract or water extract at MNTD and half MNTD (½MNTD), after which the preadipocytces were induced to form mature adipocytes. Visualisation and quantification of lipid content in mature adipocytes were carried out through oil red O staining and measurement of optical density (OD) at 520 nm, respectively. Results: The TFCs of the methanol extracts were 1.36 and 1.97 g quercetin equivalents (QE)/100 g dry weight (DW), while the TPCs of the water extracts were 5.61 and 2.73 g gallic acid equivalents (GAE)/100 g DW for var. deltoidea and var. angustilofia, respectively. The MNTDs determined for methanol and water extracts were (300.0 ± 28.3) and (225.0 ± 21.2) µg/ml, respectively, for var. deltoidea, while much lower MNTDs [(60.0 ± 2.0) µg/ml for methanol extracts and (8.0 ± 1.0) µg/ml for water extracts] were recorded for var. angustifolia. Studies revealed that the methanol extracts of both varieties and the water extracts of var. angustifolia at either MNTD or ½MNTD significantly inhibited the maturation of preadipocytes. Conclusions: The inhibition of the formation of mature adipocytes indicated that leaf extracts of F. deltoidea could have potential anti-obesity effects.
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    • ". The in vitro tests using 3T3-L1 cells revealed that 1 and 28 had the ability to inhibit differentiation of preadipocytes and to induce apoptosis in mature adipocytes . The activity of 1 is stronger than of 28 [107]. Recently it was reported that 1 administered to Zucker fa/fa rats lowered body weight and fasting plasma glucose level in obese males, but not in the females [108]. "
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    • "Corroborating these findings, after administration of XN to rats, free or conjugated IXN was present at much higher concentration in blood (5.91 mmol/L) than XN itself [9]. IXN alters folic acid transport through human trophoblasts and intestinal Caco-2 cells [10] [11], inhibits transforming growth factor beta signaling, and proinflammatory gene expression [12], modulates adipogenesis [13], has anticancer properties [14], and inhibits in vivo angiogenesis [15]. IXN scavenges physiological reactive oxygen species (ROS) as superoxide anion, hydroxyl-and peroxyl-radicals, being as effective as Trolox in inactivating hydroxyl radicals at a concentration of 5 mM in cancer cells [16]. "
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    ABSTRACT: Angiogenesis and inflammation are becoming distinguished players in the pathogenesis of many heterogeneous diseases, such as diabetes, cardiovascular disease, and cancer. Therefore, it is crucial to study new compounds that are able to modulate these events. Isoxanthohumol (IXN) is a polyphenol with antioxidant, anti-inflammatory, and antiangiogenic properties. The aim of this study was to evaluate the effects of IXN on blood vessel proliferation and maturation and describe underlying molecular mechanisms in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Angiogenic profile of IXN was analyzed by retinal angiogenesis at different time points. IXN modulation of angiogenic and inflammatory signaling pathways was evaluated by Western blotting on EC and VSMC cultures. IXN inhibited by 20% sprouting angiogenesis and decreased vascular coverage by mural cells up to 39%. IXN of 10 µM also decreased inflammatory signals, namely tumor necrosis factor alpha (TNF-α) (26 and 40%) and factor nuclear kappa B (24 and 42%) in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs). Angiogenic regulators, including vascular endothelial growth factor receptor 2 (HUVEC, 55%), angiopoietins 1 (HUVEC, 39%; HASMC, 35%), angiopoietin 2 (HUVEC, 38%), and Tie2 (HUVEC, 56%) were also inhibited by 10 µM of IXN treatments. Akt activation was reduced by 47% in HUVEC-treated cells and Erk activation was also reduced by 52 and 69% upon IXN treatment of HUVEC and HASMC. IXN seems to regulate in vivo vascular proliferation and stabilization and the EC-VSMC-inflammatory crosstalk, leaving this molecule as an interesting nutritional player for angiogenesis and inflammation-related diseases. © 2013 BioFactors, 2013.
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