Effects of Dityrosine on Lactic Acid Metabolism in Mice Gastrocnemius Muscle During Endurance Exercise via the Oxidative Stress-Induced Mitochondria Damage.

Dityrosine (Dityr) has been detected in commercial food as a product of protein oxidation and has been shown to pose a threat to human health. This study aims to investigate whether Dityr causes a decrease in lactic acid metabolism in the gastrocnemius muscle during endurance exercise. C57BL/6 mice were administered Dityr or saline by gavage for 13 weeks and underwent an endurance exercise test on a treadmill. Dityr caused a severe reduction in motion displacement and endurance time, along with a significant increase in lactic acid accumulation in the blood and gastrocnemius muscle in mice after exercise. Dityr induced significant mitochondrial defects in the gastrocnemius muscle of mice. Additionally, Dityr induced serious oxidative stress in the gastrocnemius muscle, accompanied by inflammation, which might be one of the causes of mitochondrial dysfunction. Moreover, significant apoptosis in the gastrocnemius muscle increased after exposure to Dityr. This study confirmed that Dityr induced oxidative stress in the gastrocnemius muscle, which further caused significant mitochondrial damage in the gastrocnemius muscle cell, resulting in decreased capacity of lactic acid metabolism and finally affected performance in endurance exercise. This may be one of the possible mechanisms by which highly oxidized foods cause a decreased muscle energy metabolism.

Dityrosine Aggravates Hepatic Insulin Resistance in Obese Mice by Altering Gut Microbiota and the LPS/TLR4/NF-κB Inflammatory Pathway.

SCOPE: Dityrosine is the main product of protein oxidation, which has been proved to be a threat to human health. This study aims to investigate whether dityrosine exacerbates insulin resistance by inducing gut flora disturbance and associated inflammatory responses. METHODS AND RESULTS: Mice fed with normal diet or high-fat diet (HFD) received daily gavage of dityrosine (320 µg kg-1 BW) or saline for consecutive 13 weeks. The effects of dityrosine on gut microbiota are verified by in vitro fermentation using fecal microbiota from db/m mice and db/db mice. As a result, dityrosine causes the insulin resistance in mice fed normal diet, and aggravates the effects of HFD on insulin sensitivity. Dityrosine increases the levels of lipopolysaccharide (LPS), lipopolysaccharide-binding protein (LBP), toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) but decreases levels of interleukin-10 (IL-10) in the plasma of CON and HFD-fed mice. The changes of gut flora composition caused by dityrosine are significantly correlated with the changes of inflammatory biomarkers. CONCLUSION: The effects of dityrosine on insulin resistance may be attributed to the reshaping of the gut microbiota composition and promoting the activity of the LPS/TLR4/NF-κB inflammatory pathway in HFD-induced obese individuals.

Orally administered octacosanol improves liver insulin resistance in high-fat diet-fed mice through the reconstruction of the gut microbiota structure and inhibition of the TLR4/NF-κB inflammatory pathway.

1-Octacosanol (Octa) is reported to possess many physiological properties. However, its relative mechanism has not been illustrated yet. Herein, we aimed to investigate the effect of Octa on insulin resistance in mice fed with a high fat diet (HFD) and used an in vitro simulated gastrointestinal tract to analyze its digestive behavior. The effects of Octa on the gut microbiota were verified by in vitro fermentation using the mouse fecal microbiota. As a result, the Octa monomer was digested into shortened saturated and unsaturated fatty acids (C10-C24) in the simulated gastrointestinal tract. Octa improved the fasting blood glucose (FBG), insulin resistance (IR), plasma lipids, and inflammatory response in HFD-fed mice in a dose-dependent manner. This study also suggested that a high-dose of Octa effectively decreased the levels of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in the plasma of HFD-fed mice. Octa improved the oxidative stress induced by a HFD and increased the expression of the Nrf2/ARE signaling pathway. Importantly, Octa reshaped gut microbiota through decreasing Firmicutes content and increasing Bacteroidota and Verrucomicrobiota contents at the phylum level, and the changes of intestinal flora structure caused by Octa were significantly correlated with the changes of inflammatory biomarkers. In conclusion, the effects of Octa on insulin resistance might be attributed to the reconstruction of the gut microbiota structure and inhibition of the TLR4/NF-κB inflammatory pathway in HFD-induced obese individuals.