Dietary Habits and Metabolic Health.

Dietary habits refer to the long-term dietary patterns and habits that an individual forms and maintains in their daily life [...].

Dietary Methionine Restriction Improves Gastrocnemius Muscle Glucose Metabolism through Improved Insulin Secretion and H19/IRS-1/Akt Pathway in Middle-Aged Mice.

Methionine restriction (MR) improves glucose metabolism. In skeletal muscle, H19 is a key regulator of insulin sensitivity and glucose metabolism. Therefore, this study aims to reveal the underlying mechanism of H19 upon MR on glucose metabolism in skeletal muscle. Middle-aged mice were fed MR diet for 25 weeks. Mouse islets ß cell line ß-TC6 cells and mouse myoblast cell line C2C12 cells were used to establish the apoptosis or insulin resistance model. Our findings showed that MR increased B-cell lymphoma-2 (Bcl-2) expression, deceased Bcl-2 associated X protein (Bax), cleaved cysteinyl aspartate-specific proteinase-3 (Caspase-3) expression in pancreas, and promoted insulin secretion of ß-TC6 cells. Meanwhile, MR increased H19 expression, insulin Receptor Substrate-1/insulin Receptor Substrate-2 (IRS-1/IRS-2) value, protein Kinase B (Akt) phosphorylation, glycogen synthase kinase-3ß (GSK3ß) phosphorylation, and hexokinase 2 (HK2) expression in gastrocnemius muscle and promoted glucose uptake in C2C12 cells. But these results were reversed after H19 knockdown in C2C12 cells. In conclusion, MR alleviates pancreatic apoptosis and promotes insulin secretion. And MR enhances gastrocnemius muscle insulin-dependent glucose uptake and utilization via the H19/IRS-1/Akt pathway, thereby ameliorating blood glucose disorders and insulin resistance in high-fat-diet (HFD) middle-aged mice.

Dietary Methionine Restriction Promotes Fat Browning and Attenuates Hepatic Lipid Accumulation in High-Choline-Fed Mice Associated with the Improvement of Thyroid Function.

This study aims to explore the influences of a methionine-restricted diet (MRD) on fat browning and hepatic lipid accumulation in mice fed with a high-choline diet (HCD) and their possible mechanisms. ICR mice were randomly divided into three groups and fed with a normal diet (0.86% methionine + 0.20% choline, ND), HCD (0.86% methionine + 1.20% choline), or MRD (0.17% methionine + 1.20% choline) for 90 consecutive days. We found that MRD reduced body weight and fat mass; increased heat production and ambulatory locomotor activity; reduced hepatic and plasma lipid levels, hepatic fatty infiltration area, and adipocyte volume in white and brown adipose tissue; promoted fat browning, especially upregulated gene and protein expression levels of uncoupling protein 1 (UCP1); and promoted fat catabolism and inhibited fat anabolism in the liver and adipose tissue. Moreover, MRD increased antioxidant defenses and reduced inflammatory cytokine levels in the thyroid, blood, and liver. Furthermore, MRD improved thyroid morphological structure, promoted the synthesis and secretion of thyroid hormones, and enhanced the actions of thyroid hormones on its receptor organs (liver and adipose tissue). These findings suggested that MRD promoted fat browning and attenuated hepatic lipid accumulation in HCD mice associated with the improvement of thyroid function.

Dietary Methionine Restriction Alleviates Choline-Induced Tri-Methylamine-N-Oxide (TMAO) Elevation by Manipulating Gut Microbiota in Mice.

Dietary methionine restriction (MR) has been shown to decrease plasma trimethylamine-N-oxide (TMAO) levels in high-fat diet mice; however, the specific mechanism used is unknown. We speculated that the underlying mechanism is related with the gut microbiota, and this study aimed to confirm the hypothesis. In this study, we initially carried out an in vitro fermentation experiment and found that MR could reduce the ability of gut microbiota found in the contents of healthy mice and the feces of healthy humans to produce trimethylamine (TMA). Subsequently, mice were fed a normal diet (CON, 0.20% choline + 0.86% methionine), high-choline diet (H-CHO, 1.20% choline + 0.86% methionine), or high-choline + methionine-restricted diet (H-CHO+MR, 1.20% choline + 0.17% methionine) for 3 months. Our results revealed that MR decreased plasma TMA and TMAO levels in H-CHO-diet-fed mice without changing hepatic FMO3 gene expression and enzyme activity, significantly decreased TMA levels and expression of choline TMA-lyase (CutC) and its activator CutD, and decreased CutC activity in the intestine. Moreover, MR significantly decreased the abundance of TMA-producing bacteria, including Escherichia-Shigella (Proteobacteria phylum) and Anaerococcus (Firmicutes phylum), and significantly increased the abundance of short-chain fatty acid (SCFA)-producing bacteria and SCFA levels. Furthermore, both MR and sodium butyrate supplementation significantly inhibited bacterial growth, down-regulated CutC gene expression levels in TMA-producing bacteria, including Escherichia fergusonii ATCC 35469 and Anaerococcus hydrogenalis DSM 7454 and decreased TMA production from bacterial growth under in vitro anaerobic fermentation conditions. In conclusion, dietary MR alleviates choline-induced TMAO elevation by manipulating gut microbiota in mice and may be a promising approach to reducing circulating TMAO levels and TMAO-induced atherosclerosis.

Methionine-Restricted Diet: A Feasible Strategy Against Chronic or Aging-Related Diseases.

Dietary methionine restriction (MR) has been associated with multifaceted health-promoting effects. MR is conducive to prevention of several chronic diseases and cancer, and extension of lifespan. A growing number of studies on new phenotypes and mechanisms of MR have become available in the past five years, especially in angiogenesis, neurodegenerative diseases, intestinal microbiota, and intestinal barrier function. In this review, we summarize the characteristics and advantages of MR, and current knowledge on the physiological responses and effects of MR on chronic diseases and aging-associated pathologies. Potential mechanisms, in which hydrogen sulfide, fibroblast growth factor 21, gut microbiota, short-chain fatty acids, and so on are involved, are discussed. Moreover, directions for epigenetics and gut microbiota in an MR diet are presented in future perspectives. This review comprehensively summarizes the novel roles and interpretations of the mechanisms underlying MR in the prevention of chronic diseases and aging.

Dityrosine in food: A review of its occurrence, health effects, detection methods, and mitigation strategies.

Protein and amino acid oxidation in food products produce many new compounds, of which the reactive and toxic compound dityrosine, derived from oxidized tyrosine, is the most widely studied. The high reactivity of dityrosine enables this compound to induce oxidative stress and disrupt thyroid hormone function, contributing to the pathological processes of several diseases, such as obesity, diabetes, cognitive dysfunction, aging, and age-related diseases. From the perspective of food safety and human health, protein-oxidation products in food are the main concern of consumers, health management departments, and the food industry. This review highlights the latest research on the formation pathways, toxicity, detection methods, occurrence in food, and mitigation strategies for dityrosine. Furthermore, the control of dityrosine in family cooking and food-processing industry has been discussed. Food-derived dityrosine primarily originates from high-protein foods, such as meat and dairy products. Considering its toxicity, combining rapid high sensitivity dityrosine detection techniques with feasible control methods could be an effective strategy to ensure food safety and maintain human health. However, the current dityrosine detection and mitigation strategies exhibit some inherent characteristics and limitations. Therefore, developing technologies for rapid and effective dityrosine detection and control at the industrial level is necessary.

Methionine Restriction Improves Cognitive Ability by Alleviating Hippocampal Neuronal Apoptosis through H19 in Middle-Aged Insulin-Resistant Mice.

LncRNA H19 has been reported to regulate apoptosis and neurological diseases. Hippocampal neuron apoptosis damages cognitive ability. Methionine restriction (MR) can improve cognitive impairment. However, the effect of MR on hippocampal neuronal apoptosis induced by a high-fat diet (HFD) in middle-aged mice remains unclear. For 25 weeks, middle-aged mice (C57BL/6J) were given a control diet (CON, 0.86% methionine + 4.2% fat), a high-fat diet (HFD, 0.86% methionine + 24% fat), or an HFD + MR diet (HFMR, 0.17% methionine + 24% fat). The HT22 cells were used to establish the early apoptosis model induced by high glucose (HG). In vitro, the results showed that MR significantly improved cell viability, suppressed the generation of ROS, and rescued HT22 cell apoptosis in a gradient-dependent manner. In Vivo, MR inhibited the damage and apoptosis of hippocampal neurons caused by a high-fat diet, reduced hippocampal oxidative stress, improved hippocampal glucose metabolism, relieved insulin resistance, and enhanced cognitive ability. Furthermore, MR could inhibit the overexpression of H19 and caspase-3 induced by HFD, HG, or H2O2 in vivo and in vitro, and promoted let-7a, b, e expression. These results indicate that MR can protect neurons from HFD-, HG-, or H2O2-induced injury and apoptosis by inhibiting H19.

Eugenol improves high-fat diet/streptomycin-induced type 2 diabetes mellitus (T2DM) mice muscle dysfunction by alleviating inflammation and increasing muscle glucose uptake.

Eugenol has been used in dietary interventions for metabolic diseases such as diabetes and obesity. However, the protective effect of eugenol on muscle function in diabetes is unclear. In this study, a high-fat diet (HFD) with a streptozocin (STZ) injection induced type II diabetes mellitus in a mouse model. Oral eugenol lowered blood glucose and insulin resistance of HFD/STZ-treated mice. Eugenol reduced HFD/STZ-induced muscle inflammation and prevented muscle weakness and atrophy. Eugenol administration significantly increased GLUT4 translocation and AMPK phosphorylation in skeletal muscle, thereby enhancing glucose uptake. By silencing the transient receptor potential vanilloid channel 1 (TRPV1) gene in C2C12 myotube cells, eugenol was found to increase intracellular Ca2+ levels through TRPV1, which then activated calmodulin-dependent protein kinase-2 (CaMKK2) and affected AMPK protein phosphorylation. In conclusion, eugenol is a potential nutraceutical for preventing high-glucose-induced muscle impairments, which could be explained by its mediating effects on glucose absorption and inflammatory responses in the muscle.

Dietary methionine restriction improves gut microbiota composition and prevents cognitive impairment in D-galactose-induced aging mice.

Dietary methionine restriction (MR) has been shown to delay aging and ameliorate age-related cognitive impairments. We hypothesized that changes in the gut microbiota may mediate these effects. To test this hypothesis, ICR mice subcutaneously injected with 150 mg kg-1 day-1D-galactose were fed a normal (0.86% methionine) or an MR (0.17% methionine) diet for 2 months. Multiple behavioral experiments were performed, and the gut microbiota composition, metabolite profiles related to short-chain fatty acids (SCFAs) in the feces, and indicators related to the redox and inflammatory states in the hippocampus were further analyzed. Our results indicated that MR alleviated cognitive impairment (including non-spatial memory deficits, working memory deficits, and hippocampus-dependent spatial memory deficits) and anxiety-like behavior in D-Gal-induced aging mice. Furthermore, MR increased the abundance of putative SCFA-producing bacteria such as Lachnospiraceae, Turicibacter, Roseburia, Ruminococcaceae_UCG-014, Intestinimonas, Rikenellaceae, Tyzzerella, and H2S-producing bacteria such as Desulfovibrio in feces. Moreover, MR reversed and normalized the levels of intestinal SCFAs (acetate, propionate, and butyrate) and important intermediate metabolites of the SCFAs (pyruvate, lactate, malate, fumarate, and succinate), abolished aging-induced oxidative stress and inflammatory responses, increased the levels of H2S in the plasma and hippocampus, and selectively modulated the expression of multiple learning- and memory-related genes in the hippocampus. These findings suggest that MR improved the gut microbiota composition and SCFA production and alleviated oxidative stress and inflammatory responses in the hippocampus, which might prevent cognitive impairment in D-galactose-induced aging mice.

Dietary Methionine via Dose-Dependent Inhibition of Short-Chain Fatty Acid Production Capacity Contributed to a Potential Risk of Cognitive Dysfunction in Mice.

High-methionine diets induce impaired learning and memory function, dementia-like neurodegeneration, and Alzheimer's disease, while low-methionine diets improve learning and memory function. We speculated that variations in intestinal microbiota may mediate these diametrically opposed effects; thus, this study aimed to verify this hypothesis. The ICR mice were fed either a low-methionine diet (LM, 0.17% methionine), normal methionine diet (NM, 0.86% methionine), or high-methionine diet (HM, 2.58% methionine) for 11 weeks. We found that HM diets damaged nonspatial recognition memory, working memory, and hippocampus-dependent spatial memory and induced anxiety-like behaviors in mice. LM diets improved nonspatial recognition memory and hippocampus-dependent spatial memory and ameliorated anxiety-like behavior, but the differences did not reach a significant level. Moreover, HM diets significantly decreased the abundance of putative short-chain fatty acid (SCFA)-producing bacteria (Roseburia, Blautia, Faecalibaculum, and Bifidobacterium) and serotonin-producing bacteria (Turicibacter) and significantly increased the abundance of proinflammatory bacteria Escherichia-Shigella. Of note, LM diets reversed the results. Consequently, the SCFA and serotonin levels were significantly decreased with HM diets and significantly increased with LM diets. Furthermore, HM diets induced hippocampal oxidative stress and inflammation and selectively downregulated the hippocampus-dependent memory-related gene expression, whereas LM diets selectively upregulated the hippocampus-dependent memory-related gene expression. In conclusion, dietary methionine via dose-dependent inhibition of SCFA production capacity contributed to a potential risk of cognitive dysfunction in mice.

High dietary methionine intake may contribute to the risk of nonalcoholic fatty liver disease by inhibiting hepatic H2S production.

Methionine, an essential sulfur-containing amino acid, is associated with hepatic lipid accumulation; however, the underlying mechanism is unknown. This study aimed to investigate the effects of different dietary methionine levels on hepatic lipid accumulation in mice and clarify the possible mechanisms involved. The Institute of Cancer Research (ICR) mice were fed a normal diet (ND, 0.86% methionine), high-methionine diet (HMD, 2.58% methionine), or methionine-restricted diet (MRD, 0.17% methionine) for 11 consecutive weeks. Our results showed that HMD increased the liver weight and liver index, plasma and hepatic lipid profiles, and hepatic fatty infiltration area and perirenal fat volume. In addition, HMD promoted lipid synthesis, inhibited lipid catabolism and glycolysis metabolism, reduced the activities of mitochondrial respiratory chain enzyme complexes (Ⅰ and Ⅴ) and adenosine triphosphate (ATP) production, and elevated oxidative stress and inflammation in the liver. Moreover, HMD inhibited homocysteine metabolism and significantly decreased the expression and activity of cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), thereby reducing endogenous H2S production in the liver. Interestingly, MRD reversed these adverse effects, and promoted endogenous H2S production. In conclusion, inhibition of hepatic H2S production may be the mechanism behind an increased risk of nonalcoholic fatty liver disease (NAFLD) associated with high dietary methionine intake. Therefore, it is necessary to reduce methionine intake in the daily diet to prevent NAFLD and maintain good physical health.

Oxidized Pork Induces Hepatic Steatosis by Impairing Thyroid Hormone Function in Mice.

SCOPE: Recent studies have linked high consumption of red and processed meats to an increased risk of non-alcoholic fatty liver disease, and cooking-induced oxidation of proteins and amino acids might be contributing factors. Herein, this study investigates the influence of oxidized pork and the protein oxidation biomarker dityrosine (Dityr) on hepatic steatosis in mice. METHODS AND RESULTS: Low- and high-oxidative injury pork (LOP and HOP) are freeze-dried to prepare mouse diets. Mice are fed a diet of either the control, LOP, HOP, LOP+Dityr, or Dityr for 12 weeks. HOP and Dityr intake induced oxidative stress and inflammation that impaired thyroid function and peripheral metabolism (reduced type 1 deiodinase activity) of thyroid hormones (THs). These lead to a decrease in the circulating as well as liver THs and induced hepatic steatosis. This process might be regulated through reduced TH levels and altered TH target genes and proteins related to hepatic lipid metabolism that ultimately inhibited hepatic energy metabolism, as indicated by increased hepatic lipid synthesis, decreased hepatic lipid catabolism, and fatty acid oxidation. CONCLUSION: HOP intake could induce hepatic steatosis by impairing TH function. Dityr plays an important role in the HOP-induced harmful effects.

Metabolomics Based on 1H-NMR Reveal the Regulatory Mechanisms of Dietary Methionine Restriction on Splenic Metabolic Dysfunction in Obese Mice.

Methionine restriction (MR) has been reported to have many beneficial health effects, including stress resistance enhancement and lifespan extension. However, the effects of MR on the splenic metabolic dysfunction induced by obesity in mice remain unknown. This study aimed to investigate the scientific problem and clarify its possible mechanisms. C57BL/6J mice in the control group were fed a control diet (0.86% methionine, 4.2% fat) for 34 weeks, and others were fed a high-fat diet (0.86% methionine, 24% fat) for 10 weeks to establish diet-induced obese (DIO) mouse models. Then, the obtained DIO mice were randomly divided into two groups: the DIO group (DIO diet), the DIO + MR group (0.17% methionine, 24% fat) for 24 weeks. Our results indicated that MR decreased spleen weight, and spleen and plasma lipid profiles, promoted lipid catabolism and fatty acid oxidation, glycolysis and tricarboxylic acid cycle metabolism, and improved mitochondrial function and ATP generation in the spleen. Moreover, MR normalized the splenic redox state and inflammation-related metabolite levels, and increased plasma levels of immunoglobulins. Furthermore, MR increased percent lean mass and splenic crude protein levels, activated the autophagy pathway and elevated nucleotide synthesis to maintain protein synthesis in the spleen. These findings indicate that MR can ameliorate metabolic dysfunction by reducing lipid accumulation, oxidative stress, and inflammation in the spleen, and the mechanism may be the activation of autophagy pathway.

Oxidized Pork Induces Disorders of Glucose Metabolism in Mice.

SCOPE: Consumption of red meat, particularly processed red meat, has been reported to be associated with type 2 diabetes risk, and oxidized proteins and amino acids may be involved in this process. This study explores the effects of pork with varying degrees of oxidative injury caused by cooking on glucose metabolism in mice. METHODS AND RESULTS: Cooked pork is freeze-dried to prepare animal feed. Mice are fed either a control diet (CON), a low- (LOP), or a high-oxidative injury pork diet (HOP) for 12 weeks. Intake of HOP causes hyperglycemia, hypoinsulinemia, and impaired glucose tolerance, indicating a glucose metabolism disorder. Accumulation of oxidation products increases oxidative stress and inflammatory response, which impairs pancreatic islet ß cells function and reduces insulin secretion. Moreover, HOP-mediated hyperglycemia can be partly attributed to elevated hepatic glucose output, as indicated by increased gluconeogenesis and glycogenolysis, and decreased glycolysis and glycogen content. Changes in these processes may be regulated by reduced insulin levels and suppression of the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and its downstream signaling molecules. CONCLUSION: HOP intake induces disorders of glucose metabolism by impairing pancreatic insulin secretion and increasing hepatic glucose output. Protein oxidation plays a key role in abnormal glucose metabolism induced by HOP.

Chemical Space Charting of Different Parts of Inula nervosa Wall.: Upregulation of Expression of Nrf2 and Correlated Antioxidants Enzymes.

The edible and medicinal part of Inula nervosa Wall. (Xiaoheiyao) is confined to its root without sufficient phytochemical and biological investigation. In this study, the secondary metabolites of root, stem, leaf, and flower of I. nervosa Wall. were visualized using Global Natural Products Social Molecular Networking (GNPS), MolNetEnhancer, XCMS(xcmsonline.scripps.edu) analysis, and `ili mapping based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) data to reveal their chemical differences. Among the 11 kinds of chemical repertoires annotated by MolNetEnhancer and 16 hits against the GNPS library, 10-isobutyryloxy-8,9-epoxythymol isobutyrate (1) was revealed as the most dominant and responsible marker between the roots and the other parts. Moreover, a battery of unique MS features as well as differential markers were discovered from different parts of the plant. The chemical differences contribute to the bioactivity differences, which presented in the 2,2-diphenyl-1-picryl-hydrazyl (DPPH)assay and H2O2-insulted HepG2 cells and were in significant correlations with the contents of 1. real-time reverse transcription polymerase chain reaction (RT-PCR)results demonstrated that I. nervosa Wall. extracts upregulated the mRNA expression of nuclear factor E2-related factor 2(Nrf2), heme oxygenase 1(HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), manganese superoxide dismutase (MnSOD), and glutamate-cysteine ligase catalytic subunit (GCLC) actors involved in antioxidative response in H2O2-challenged HepG2 cells. These findings support the roots of I. nervosa Wall. as active parts of Xiaoheiyao, and also indicate the potential antioxidant activities of other parts.

Sea Cucumber Peptides Improved the Mitochondrial Capacity of Mice: A Potential Mechanism to Enhance Gluconeogenesis and Fat Catabolism during Exercise for Improved Antifatigue Property.

Sea cucumber promotes multifaceted health benefits. However, the mechanisms of sea cucumber peptides (Scp) regulating the antifatigue capacity is still unknown. The present study is aimed at further elucidating the effects and mechanisms of Scp on the antifatigue capacity of mice. At first, C57BL/6J mice were assigned into four groups named Con, L-Scp, M-Scp, and H-Scp and received diets containing Scp (0%, 0.15%, 0.3%, and 0.5%, respectively) for continuous 30 days. On the 21th day, a fore grip test was conducted on mice. On the 25th day, a rotating rod test was conducted on mice. On the 30th day, the quantities of glycogen and mitochondrial DNA (mtDNA) were determined in 8 random mice and another 8 mice were forced to swim for 1 hour before slaughter for detecting biochemical indicators. It was observed that the Scp groups significantly prolonged the running time in rotarod, increased forelimb grip strength, improved lactic acid (LD) and urea nitrogen (BUN) levels in the serum, decreased lactic dehydrogenase (LDH) and glutamic oxalacetic transaminase (GOT) activities in the serum, increased blood glucose (BG) and glycogen (GN) levels in the liver and skeletal muscle after swimming, increased the activity of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in the skeletal muscle and heart, and improved antioxidant capacity. Furthermore, Scp treatment significantly elevated the mRNA and protein relative levels of power-sensitive factors, lipid catabolism, and mitochondrial biogenesis and significantly upregulated mRNA levels of gluconeogenesis. Besides, mtDNA before the swimming test was increased in the three Scp groups. These results show that Scp treatment has antifatigue capacity. Furthermore, these results suggest that improved energy regulation and antioxidant capacity may be the result of improved mitochondrial function.

Dietary Methionine Restriction Ameliorated Fat Accumulation, Systemic Inflammation, and Increased Energy Metabolism by Altering Gut Microbiota in Middle-Aged Mice Administered Different Fat Diets.

Diet greatly influences gut microbiota. Dietary methionine restriction (MR) prevents and ameliorates age-related or high-fat-induced diseases and prolongs life span. This study aimed to reveal the impact of MR on gut microbiota in middle-aged mice with low-, medium-, high-fat diets. C57BL/6J mice were randomly divided into six groups with different MR and fat-content diets. Multiple indicators of intestinal function, fat accumulation, energy consumption, and inflammation were measured. 16S rRNA gene sequencing was used to analyze cecal microbiota. Our results indicated that MR considerably reduced the concentrations of lipopolysaccharide (LPS) and increased short-chain fatty acids (SCFAs) by upregulating the abundance of Corynebacterium and SCFA-producing bacteria Bacteroides, Faecalibaculum, and Roseburia and downregulating the LPS-producing or proinflammatory bacteria Desulfovibrio and Escherichia-Shigella. The effect of MR on LPS and SCFAs further reduced fat accumulation and systemic inflammation, enhanced heat production, and mediated the LPS/LBP/CD14/ TLR4 pathway to strength the intestinal mucosal immunity barrier in middle-aged mice.

Dietary methionine restriction improves the impairment of cardiac function in middle-aged obese mice.

Dietary methionine restriction (MR) has been reported to extend lifespan, reduce obesity and decrease oxidative damage to mtDNA in the heart of rats, and increase endogenous hydrogen sulfide (H2S) production in the liver and blood. H2S has many potential benefits in the pathophysiology of the cardiovascular system. MR also increases the level of homocysteine (Hcy) in the liver and plasma, but elevated plasma Hcy is a risk factor for cardiovascular disease. Therefore, this study aimed to determine the effect of MR on cardiac function and metabolic status in obese middle-aged mice and its possible mechanisms. C57BL/6J mice (aged approximately 28 weeks) were divided into six dietary groups: CON (0.86% methionine + 4% fat), CMR40 (0.52% methionine + 4% fat), CMR80 (0.17% methionine + 4% fat), HFD (0.86% methionine + 24% fat), HMR40 (0.52% methionine + 24% fat) and HMR80 (0.17% methionine + 24% fat) for 15 consecutive weeks. Our results showed that 80% MR improves systolic dysfunction in middle-aged obese mice and enhances myocardial energy metabolism. 80% MR also reduces myocardial oxidative stress and improves inflammatory response. In addition, 80% MR increased mice Hcy levels and activated remethylation and transsulfur pathways of Hcy and promoted endogenous H2S production in the heart. 40% MR has the same trend, but is not significant. Moreover 40% MR at variance with 80% MR, did not decrease the body weight in both control and high-fat diet mice. These findings suggest that MR can improve myocardial energy metabolism, reduce heart inflammation and oxidative stress by increasing cardiac H2S production, and improve cardiac dysfunction in middle-aged obese mice.

Dityrosine suppresses the cytoprotective action of thyroid hormone T3 via inhibiting thyroid hormone receptor-mediated transcriptional activation.

Dityrosine (Dityr) is the most common oxidized form of tyrosine. In the previous studies of mice treated with dityrosine, cell death in the pancreas, kidneys, and liver was detected in the presence of enhanced plasma triiodothyronine (T3) content. Due to its structural similarity with the thyroid hormone T3, we hypothesized that dityrosine might disrupt T3-dependent endocrine signaling. The cytotoxic effect of dityrosine was studied in C57BL/6 mice by gavage with a dityrosine dose of 320 µg per kg per day for 10 weeks. Cell death in the liver was detected in the presence of enhanced plasma thyroid hormone content in mice treated with dityrosine. The antagonistic effect of dityrosine on T3 biofunction was studied using HepG2 cells. Dityrosine incubation reduced T3 transport ability and attenuated the T3-mediated cell survival via regulation of the PI3k/Akt/MAPK pathway. Furthermore, dityrosine inhibited T3 binding to thyroid hormone receptors (TRs) and suppressed the TR-mediated transcription. Dityrosine also downregulated the expressions of T3 action-related factors. Taken together, this study demonstrates that dityrosine inhibits T3-dependent cytoprotection by competitive inhibition, resulting in downstream gene suppression. Our findings offer insights into how dityrosine acts as an antagonist of T3. These findings shed new light on cellular processes underlying the energy metabolism disorder caused by dietary oxidized protein, thus contributing to a better understanding of the diet-health axis at a cellular level.

Oxidized Pork Induces Oxidative Stress and Inflammation by Altering Gut Microbiota in Mice.

SCOPE: Reduced digestibility of foods containing oxidized proteins and the subsequent excessive accumulation of undigested components in the colon may cause changes in the intestinal flora composition. This study evaluates the characteristics of this change and the potential adverse effects on organisms. METHODS AND RESULTS: Pork is cooked using sous-vide or at high temperature and pressure (HTP), then freeze-dried, resulting in different levels of oxidized damage. Mice are fed diets containing low- (LOP), medium- (MOP), or high-oxidative damage pork (HOP) for 12 weeks. HOP intake increases mice body weight, induces inflammatory response, and causes oxidative stress, as indicated by the accumulation of oxidative products. Increased serum LPS levels and downregulation of tight junction-related genes in the mucosa suggest mucosal barrier damage. Alterations in the cecal microbiota include reduced relative abundance of the mucin-degrading bacteria Akkermansia, beneficial bacteria Lactobacillus and Bifidobacterium, and H2 S-producing bacteria Desulfovibrio and increased relative abundance of the pro-inflammatory bacteria Escherichia-Shigella and pathobiont Mucispirillum. CONCLUSION: HOP intake causes the accumulation of oxidative products, increases body weight, damages the intestinal barrier, and induces oxidative stress and inflammatory response, likely by altering gut microbiota through protein oxidation (POX).