- Metabolic syndrome is a problem affecting people around the world. In a number of studies, soy intake has been documented to possess antidiabetic and anticardiovascular effect. My project is focused on the impact of the intake of compounds found within soy, the isoflavones, their impact on metabolic syndrome symptoms, and the underlying mechanisms involved.
In study one, we aimed to determine the effect of soy product on weight gain and adiposity in male C57BL/6 mice. Six-week-old mice were put in a low-fat diet (LF), high fat diet (HF), or high fat diet plus Novasoy, an isoflavones-containing dietary supplement (HF+NS) for 10 weeks. At week 10, metabolic syndrome symptoms including obesity, high blood glucose, and hepatic lipid accumulation were observed in HF diet fed mice. However, NS intake significantly decreased body weight gain, baseline blood glucose level, and hepatic lipid accumulation (p<0.05). To further investigate the effect of isoflavone supplement intake on HF diet-induced metabolic syndrome, a custom-designed gene array was utilized to determine hepatic gene expression related to lipid metabolism, glucose metabolism, and inflammation. Relative expression of the mRNA for hormone sensitive lipase (Hsl), which catalyzes triglyceride hydrolysis, was significantly increased in NS fed mice, compared to HF fed mice. Expression of the mRNA encoding carnitine palmitoyltransferase 1 alpha (Cpt1α), the rate limiting enzyme of lipid β oxidation, was significantly lowered when NS was added to HF diet.
To follow up study one, mouse study two was conducted to determine whether consumption of the dominant soy isoflavones compounds, genistein and daidzein, influence metabolic syndrome similarly or differently, and to further investigate the underlying mechanism. C57BL/6J mice were fed low fat (LF), western diet (WD), WD containing 0.16% (w/w) of genistein (WD+G) or daidzein (WD+D) for 10 weeks. Surprisingly, intake of WD+G and WD+D significantly decreased food intake and body weight, compared to WD-fed mice (185%±10%, 112%±9%, and 150%±7% percentage weight gain in WD-, WD+G- and WD+D-fed mice, vs. LF-fed mice respectively). Genistein-fed mice had a reduced area under the curve (60-120mins) in a glucose tolerance test (p<0.05). Furthermore, gene array profiling in genistein or daidzein fed mice indicate that genistein and daidzein consumption regulate gene expression related to hepatic lipid metabolism, carbohydrate metabolism, and inflammation. Signaling pathways such as LXR/RXR and FXR/RXR were significantly activated in genistein or daidzein fed mice.
Since a more potent effect on body weight was observed in genistein- fed mice in study II, compared to NS-fed mice, we designed study III, to determine the effect of NS on WD induced metabolic syndrome symptoms, especially body weight gain. Study III demonstrated that the reduction of body weight gain in WD+NS-fed mice was less than WD+G-fed mice.
To determine if LXR was activated by genistein or daidzein, transient transfection-luciferase assays were utilized to determine the binding affinity of genistein or daidzein on LXRE regulatory elements. Furthermore, mouse embryonic fibroblast cells devoid of, or expressing LXRα were used to determine whether LXR is involved in the effect of isoflavone on lipid metabolism related gene expression.
In summary, the results of in-vivo and in-vitro studies suggest that the beneficial effects observed on weight gain and lipid metabolism observed in C57BL/6J mice due to isoflavone consumption are partly due to LXR-dependent mechanism.