Dietary genistein inhibits methylglyoxal‐induced advanced glycation end products formation in high‐fat diet‐fed mice

Abstract

The formation and accumulation of advanced glycation end products (AGEs) was considered as a major pathogenic link between hyperglycemia and diabetes‐related complications. Methylglyoxal (MGO), as an important precursor of AGEs, circulates at high concentration in diabetic patients's blood and is linked to the development of diabetes chronic complications. In the present study, we investigated whether long‐term treatment of MGO plus high‐fat diet can cause accumulation of protein glycation in mice and whether dietary genistein can prevent the formation of AGEs and ameliorate high‐fat plus MGO induced metabolic syndrome. Our results indicate that chronic high‐fat plus MGO administration (0.12–0.2% in drinking water for 18 weeks) significantly elevates the levels of MGO and AGEs in mouse plasma, liver and kidney, and cause fatty liver. Dietary genistein treatment (0.067% and 0.2% in high‐fat diet) significantly ameliorates high‐fat plus MGO‐induced fatty liver and metabolic syndrome, such as lowering body weight gain, plasma levels of glucose, cholesterol, aspartate transaminase (AST), alanine transaminase (ALT), and liver triglyceride levels. Moreover, genistein administration also significantly decreases the levels of MGO and AGEs. Further mechanistic studies demonstrate that genistein could trap MGO in mice to form mono‐MGO‐genistein adduct. In addition, genistein could regulate expressions of glyoxalase I and II, and both catalytic and modifier subunits of glutamate‐cystein ligase to promote the detoxification of MGO. Furthermore, genistein down‐regulates the expression of the receptor of AGEs (RAGE) to inhibit the AGEs‐RAGE pathway.Support or Funding InformationThis work was supported by USDA‐NIFA grants 2012‐38821‐20012.