Xanthohumol improves dysfunctional glucose and lipid metabolism in diet-induced obese C57BL/6J mice

Abstract

Xanthohumol (XN) is a prenylated flavonoid found in hops (Humulus lupulus) and beer. The dose-dependent effects of XN on glucose and lipid metabolism in a preclinical model of metabolic syndrome were the focus of our study. Forty-eight male C57BL/6J mice, 9 weeks of age, were randomly divided into three XN dose groups of 16 animals. The mice were fed a high-fat diet (60% kcal as fat) supplemented with XN at dose levels of 0, 30, or 60 mg/kg body weight/day, for 12 weeks. Dietary XN caused a dose-dependent decrease in body weight gain. Plasma levels of glucose, total triglycerides, total cholesterol, and MCP-1 were significantly decreased in mice on the 60 mg/kg/day treatment regimen. Treatment with XN at 60 mg/kg/day resulted in reduced plasma LDL-cholesterol (LDL-C), IL-6, insulin and leptin levels by 80%, 78%, 42%, and 41%, respectively, compared to the vehicle control group. Proprotein Convertase Subtilisin Kexin 9 (PCSK-9) levels were 44% lower in the 60 mg/kg dose group compared to the vehicle control group (p ≤ 0.05) which may account for the LDL-C lowering activity of XN. Our results show that oral administration of XN improves markers of systemic inflammation and metabolic syndrome in diet-induced obese C57BL/6J mice.

Keywords: C57BL/6J mice; Lipidomics; Metabolic syndrome; Obesity; PCSK9; Xanthohumol.

Fig. 1

Weekly body weights (A) and liver/body weight ratios (B) of male mice fed a high-fat diet with no XN (control), with 30 mg XN/kg body weight/day (low XN), or 60 mg XN/kg body weight/day (high XN) for 12 weeks. Values are expressed as mean ± SEM of 16 mice per group. Asterisks denote significantly different from the control group, p ≤ 0.05.

Fig. 2

Effects of dietary XN on plasma glucose (A), triglyceride (B), total cholesterol (C), HDL cholesterol (D), and LDL-C (E) levels of male mice fed a high-fat diet for 12 weeks. Values are expressed as mean ± SEM of 16 mice per group. Asterisks denote significantly different from the control group, p ≤ 0.05.

Fig 3

Effects of dietary XN on plasma levels of MCP-1 (A) and IL-6 (B) in male mice fed a high-fat diet for 12 weeks. Values are expressed as mean ± SEM of 16 mice per group. Asterisks denote significantly different from the control group, p ≤ 0.05.

Fig 4

Effects of dietary XN on plasma insulin (A), plasma leptin (B), and plasma PCSK9 (C) levels of male mice fed a high-fat diet for 12 weeks. Values are expressed as mean ± SEM of 16 mice per group. Asterisks denote significantly different from the control group, p ≤ 0.05.

Fig. 5

Lipid profiling and data processing using MetaboAnalyst 3.0. (A) Heat map revealing XN-induced changes in the relative levels of the top 34 triglyceride (TG) species ranked by one-way ANOVA followed by Fisher’s LSD post hoc analysis (p<0.01) to retain the most contrasting patterns. Data were normalized relative to the internal standard (TG51:0) and then Pareto-scaled. Color in the heat map reflects the relative TG abundance level with red being higher, and blue lower, than the mean value (the color-coded scale is derived from the Z-score). (B) The sum of chromatographic peak intensities of TGs relative to the peak intensity of the internal standard (Total TGs/TG51:0), averaged across liver samples within each treatment group (n=16/group, mean ± SEM). Hepatic TG levels in low and high XN groups are significantly different from controls (p<0.0001).