Diet and food supplements are of increasing interest in view of their potential in obesity management. Xanthohumol (XN) is a prenylated flavonoid found in hops, which have been used since ancient times as a medicinal plant. Traditional medicinal indications included the treatment of anxiety and insomnia, mild pain reduction or combating dyspepsia.[1] Today, hops are used in the manufacturing of beer and female infertile plants, e.g. Humulus lupulus L, are cultivated especially for brewing. Biologically active substances, which are important for brewing, are concentrated inside hop cones in lupulin glands which contain hop resins, bitter acids, essential oils and prenylated flavonoids. For humans, beer is the major dietary source of XN. The beer content of XN varies significantly depending on the type of beer (in the range of 0.052–0.628 mg/l).[2]

XN has also been proven to exert antioxidative, chemopreventive, and anti-inflammatory effects.[3] It inhibits metabolic activation of food-borne carcinogens,[4] induces phase 2 enzymes related to detoxification of xenobiotics,[5] inhibits the PGE2 or NO production (linked to prevention of carcinogenesis),[6-8] exerts anti-tumour activity in hypoxic tumour cells.[9] Recent studies investigating XN have also focused on the prevention and treatment of cancer.[10,11] XN has been shown to block T-cell lymphoblastic lymphomagenesis through reduction of STAT5 phosphorylation and gene up-regulated in the non-obese-diabetic STAT5bTg mice.[12] Xanthohumol also inhibits the proliferation of lymphoma cells and IL-2 induced proliferation and cell cycle progression in mouse splenic T cells.[13] XN exhibits anti-proliferative activity against breast, colon and ovarian cancer cell lines and is a potent inducer of chemoprevention enzymes regulated by the antioxidant response element.[14,15] So called ‘carcinoid’ cancer cell lines have also been treated with XN and this showed antiproliferative effects.[16]

Furthermore, the female benefits of hop extracts are under investigation for their oestrogenic and are being used by women as dietary supplements and alternatives to conventional hormone replacement therapy for the management of menopausal hot flushes.[17] One group investigated the pharmacokinetics of XN together with other three prenylated phenols following oral administration to menopausal women and reported that short-term consumption of a chemically and biologically standardized preparation of spent hops is safe for women and that once daily dosing might be appropriate. Xanthohumol and the other prenylated phenols showed long half-lives but no acute toxicity.[18]

There is some evidence, including in vitro and animal studies that XN might exert beneficial effect in hyperlipidaemia. XN inhibits diacylglycerol acyltransferase (DGAT) and the expression of DGAT or microsomal triglyceride transfer protein (MTP) related to the lowering effects of triglyceride and apolipoprotein B.[19, 20]

XN has been suggested to have anti-atherogenic bioactivity as it is reported to decrease apolipoprotein B (apoB) secretion, inhibit triglyceride (TG) synthesis and prevent LDL oxidation in vitro.[21] Furthermore, previous studies showed that XN reduced plaque formation in aortic lesions via reduced lipogenesis and increased faecal cholesterol excretion in apolipoprotein (apoE)-deficient mice.[22] Moroever, XN has been reported to increase HDL cholesterol via cholesteryl ester transfer protein (CETP) inhibition in a CETP-transgenic mouse model.[23]

Previous studies [20, 24] have shown that XN inhibits diacylglycerol acyltransferase (DGAT) activity or the expression of DGAT or microsomal triglyceride transfer protein in HepG2 cells. Those activities suggest that XN exerts TG lowering effect and amelioration of metabolic disorders in viscera. In 3T3-L1 adipocytes, Yang et al. reported reduced lipid content and decreased adipocyte marker proteins after incubation with XN.[25] However, there have not been sufficient experiments to allow us to ascertain the molecular mechanism through which XN ameliorates metabolic disorders in vivo. Nozawa, [3] found that XN activated farnesoid X receptor (FXR) in vitro and modulated genes involved in lipid or glucose metabolism in mice.

Hirata et al recently investigated the effects of XN on reverse cholesterol transport in vivo and HDL cholesterol levels using a hamster model. They showed that XN improves the cholesterol efflux capacity of HDL and further enhanced in vivo reverse cholesterol transport from macrophages to faeces in hamsters. They also suggested that it may be possible to extend these findings to humans, since hamsters, like humans, express CETP, suggesting that they have a similar RCT system to humans.[26]

Another group demonstrated that addition of XN to western-type diet ameliorates atherosclerotic plaque formation in ApoE−/− mice by positively affecting plasma cholesterol and MCP-1 concentrations and hepatic lipid metabolism via activation of AMP-activated protein kinase (AMPK). Therefore, the atheroprotective effects of XN might be attributed to combined beneficial effects on plasma cholesterol and monocyte chemoattractant protein 1 concentrations and hepatic lipid metabolism via activation of AMP-activated protein kinase.[27]

Increasing cases of obesity has become a serious social problem in developed countries especially as obesity is closely related to the development of various lifestyle diseases.[28,29] Obesity develops when energy intake, in the form of food, exceeds energy expenditure [30] and is primarily characterized by excessive adiposity.[31] There are two functionally and morphologically distinct types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT), both of which are mediators of energy homeostasis. In response to specific stimuli, WAT can acquire brown-like characteristics, which is called “beiging” and has been demonstrated in vivo [32] and in vitro [33] to improve the metabolic profile and increase thermogenesis.

There is some evidence derived from in vitro and animal studies that XN exerts anti-obesity effects, even if some controversy still exits.

Xanthohumol (XN) has been reported to exert anti-obesity effects in Zucker rats [34,35] and in various mouse strains.[3,36,37] Miranda et al.[37] demonstrated that XN has bioactivities potentially useful for countering the metabolic aberrations of Metformin. In details, they showed that treating high fat diet (HFD)-fed C57BL/6 J mice orally with XN (60 mg/kg/day) reduced their plasma low-density lipoprotein-cholesterol (LDL-c, −80%), interleukin-6 (IL-6, −78%), HOMA-IR (−52%), leptin (−41%), and plasma levels of the LDL receptor-degrading enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) (−44%) levels compared to those of vehicle/HFD control. The same group found that XN and its hydrogenated derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN) improve glucose tolerance and cognitive function in HFD-fed mice. Unlike XN, DXN and TXN are unable to form the estrogenic metabolite, 8-PN, and they themselves have negligible affinity for estrogen receptors.[38] Therefore, the XN derivatives DXN and TXN have potential to prevent or treat the neuro-metabolic impairments associated with HFD-induced obesity and metformin without risk of liver injury and adverse oestrogenic effects.

Takahashi and collegues, in their recent study in animals, observed that dietary purified XN exerted anti-obesity effects by regulating lipid metabolism and inhibiting intestinal fat absorption in KK-Ay mice, thus, they suggested that XN may exert anti-obesity effects.[39] Another team showed that XN suppressed the increase in body weight, mesenteric WAT, liver weight, and triacylglycerol levels in the plasma and liver through regulation of hepatic fatty acid metabolism and inhibition of intestinal fat absorption in Wistar rats fed a high-fat diet.[34] The anti-obesity effects of XN are partly mediated by AMPK signalling pathway suggesting that XN may have potential therapeutic implications for obesity. Yang and collegues confirmed the anti-adipogenic effects of XN under in vitro conditions.[40] Conversely, Mendes and colleagues claimed that XN does not improve the metabolic profile linked to obesity as XN may reduce adipocyte number, contributing to adipocyte hypertrophy.[41]

The prevalence of T2DM, which is often associated to obesity, has increased dramatically in the last decades. T2DM is a chronic, multifactorial and progressive disease, which affects more than 300 million people worldwide. Diabetes is characterized by hyperglycemia due to a deficiency in insulin production and/or its resistance, which contributes to endothelial dysfunction, resulting in macro and microvascular complications.[42,43] Imbalance in kidney and heart neovascularization is seen in T2DM patients. Costa and colleagues reported that XN consumption reduced angiogenesis, vascular endothelial growth-factor receptor (VEGFR)-2 expression/activity, levels of VEGF-B and its receptors (i.e. VEGFR1 and neuropilin-1), VEGF-A and phosphofructokinase-2/fructose-2,6-bisphosphatase-3 enzyme expression, a metabolic marker present in endothelial tip cells in T2DM mice kidney.[44] Altogether, these findings suggest that XN prevent angiogenic impairment and metabolic pathways that are implicated in the pathogenesis of T2DM, being promising compounds to mitigate the increasing number of diabetic patients and inherent health care costs. Another study by Costa and colleagues in the same year[45] found that XN protects mice against the development of T2DM metabolic-related complications. XN was reported to reduce body weight gain, prevent insulin resistance and modulate lipid and glucose metabolic pathways, being these effected mediated by a metabolic switch from fatty acid synthesis to oxidation and by promoting muscle glucose uptake. Furthermore, Nozawa, in their in vitro and in vivo study, reported potential beneficial effects of XN on amelioration of metabolic disorders via farnesoid X receptor (FXR) action and showed the possibility for developing such FXR modulators as functional nutrients in the therapy or prevention of metabolic syndromes.[3]

Legette et al. recently conducted a study in healthy men and women to determine basic pharmacokinetics (PK) parameters for XN with the aim to establish dose-concentration relationships and to predict dose-effect relationships in humans diagnosed with metabolic syndrome.[34] To our knowledge, this is the first study that reports human PK parameters for XN. Xanthohumol PK shows a distinct biphasic absorption pattern with XN and isoxanthohumol (IX) conjugates being the major circulating metabolites following oral consumption of XN in humans. XN metabolism appears to be similar between animals and humans, thus allowing for translation of animal study findings to future clinical work. Based on these and previous findings [34,46] the selection of effective doses to be utilized in future clinical studies aimed at improving lipid and glucose metabolism in humans diagnosed with metabolic syndrome should be possible.

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