Genistein Inhibits Protein Glycation in Healthy and Pre-Obese Mice Treated With High-Fat Diet via Trapping and Activating the Detoxification Pathways of Methylglyoxal

Abstract

Abstract Objectives High levels of methylglyoxal (MGO) and advanced glycation end products (AGEs) play important roles in the pathogenesis of diabetes and other chronic diseases. This study aimed to investigate the underlying mechanisms that dietary genistein inhibits the accumulations of MGO and AGEs in healthy and pre-obese mice treated with high-fat diet. Methods In Study 1, male C57BL/6J mice (6-wk old, n = 15) were fed a low-fat (LF) diet (10% fat energy) or a very-high-fat diet (VHF, 60% fat energy) alone or including 0.25% genistein (VHF-G) for 16 weeks. In study 2, the mice were fed the LF diet (LF) or HF diet alone (HF, 45% fat energy) or in combination with up to 0.2% MGO in water (HFM), and 0.067% (HFM-GL) or 0.2% (HFM-GH) dietary genistein for 18 weeks. In study 3, the mice were induced with obesity after being fed HF diet (45% fat energy) for 9 weeks before being administrated with genistein at two doses of 0.1% (G 0.1) and 0.2% (G 0.2) in the HF diet for additional 19 weeks. The concentrations of MGO and AGEs in mouse samples and other metabolic data of the mice were measured. Moreover, the potential mechanisms of genistein on lowering MGO and AGEs were investigated. Results The plasma MGO concentration in VHF-G mice was 52% lower than that in VHF mice. Also, the AGE levels in plasma, liver, and kidney of VHF-G mice were 73%, 52%, and 49% lower than in the VHF group (Study 1). Similarly, the concentrations of plasma MGO and AGEs in plasma, liver, and kidney of HFM-GH mice were 33.5%, 49%, 69%, and 54% lower than in HFM mice (Study 2). Moreover, dietary genistein at 0.2% (G 0.2) significantly decreased the MGO levels in plasma and liver by 43.9% and 30.4% compared with HF mice and decreased the AGE level in the kidney by 48.3% in pre-obese mice (Study 3). Mechanistically, genistein lowered MGO concentrations and inhibited AGE formation through direct trapping both endogenous and exogenous MGO to form the MGO adducts and activating the MGO detoxification systems of glyoxalase and aldose reductase (AR) to lower MGO levels indirectly in vivo. Conclusions The present studies provide novel insights into the anti-obesity and anti-glycation roles of dietary genistein in mice. However, whether genistein could exert similar beneficial effects in humans needs to be further investigated. Funding Sources USDA/NIFA.