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

Abstract

ScopeDityrosine 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 resultsMice 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.ConclusionThe 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.

Effects of Mulberry Leaf Fu Tea on the Intestines and Intestinal Flora of Goto-Kakizaki Type 2 Diabetic Rats

“…However, after oral administration of MFT extract to GK rats, there was a significant reduction in the height of the duodenal villi. This LPS is a biomolecule that can trigger the body's inflammatory response, and its role is to release inflammatory mediators, ultimately leading to insulin resistance [45]. We measured the levels of the pro-inflammatory substance LPS and the inflammatory mediator Il-1β in the serum.…”

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

“…It has been established that food-derived Dityr may be linked to the development of chronic noncommunicable health threats, including energy metabolism disorders, − hepatic steatosis, and brain damage. − Mechanistic studies have confirmed that oxidative stress may be one of the key factors in Dityr-induced health issues, leading to mitochondrial function damage. − Given these findings, investigating the relationship between Dityr and oxidative stress is currently a highly relevant research topic. Recent studies on inflammation mechanisms have also confirmed that oxidative stress not only directly induces damage to cellular components, such as lipids, proteins, and nucleic acids, − but also acts as an inducer of inflammation …”

“…After highly oxidized food enters the gastrointestinal tract, a large amount of free Dityr is released from the peptide chain and absorbed by the gastrointestinal tract by the action of the digestive system . It has been established that food-derived Dityr may be linked to the development of chronic noncommunicable health threats, including energy metabolism disorders, − hepatic steatosis, and brain damage. − Mechanistic studies have confirmed that oxidative stress may be one of the key factors in Dityr-induced health issues, leading to mitochondrial function damage. − Given these findings, investigating the relationship between Dityr and oxidative stress is currently a highly relevant research topic.…”