4-hydroxy-2-nonenal and Weight-Gain

As significant differences between sexes were found in the susceptibility to alcoholic liver disease in human and animal models, it was the aim of the present study to investigate whether female mice also are more susceptible to the development of non-alcoholic fatty liver disease (NAFLD). Male and female C57BL/6J mice were fed either water or 30% fructose solution ad libitum for 16 wks. Liver damage was evaluated by histological scoring. Portal endotoxin levels and markers of Kupffer cell activation and insulin resistance, plasminogen activator inhibitor 1 (PAI-1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK ) were measured in the liver. Adiponectin mRNA expression was determined in adipose tissue. Hepatic steatosis was almost similar between male and female mice; however, inflammation was markedly more pronounced in livers of female mice. Portal endotoxin levels, hepatic levels of myeloid differentiation primary response gene (88) (MyD88) protein and of 4-hydroxynonenal protein adducts were elevated in animals with NAFLD regardless of sex. Expression of insulin receptor substrate 1 and 2 was decreased to a similar extent in livers of male and female mice with NAFLD. The less pronounced susceptibility to liver damage in male mice was associated with a superinduction of hepatic pAMPK in these mice whereas, in livers of female mice with NAFLD, PAI-1 was markedly induced. Expression of adiponectin in visceral fat was significantly lower in female mice with NAFLD but unchanged in male mice compared with respective controls. In conclusion, our data suggest that the sex-specific differences in the susceptibility to NAFLD are associated with differences in the regulation of the adiponectin-AMPK-PAI-1 signaling cascade.

Topics: Adiponectin; Aldehydes; AMP-Activated Protein Kinases; Animals; Disease Susceptibility; Endotoxins; Energy Intake; Fatty Liver; Female; Fructose; Humans; Inflammation; Insulin; Intramolecular Oxidoreductases; Lipid Metabolism; Liver; Male; Mice; Non-alcoholic Fatty Liver Disease; Phosphorylation; Plasminogen Activator Inhibitor 1; Prostaglandin-E Synthases; Receptors, Adiponectin; Sex Characteristics; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Weight Gain

To test the hypothesis that the inducible nitric oxide synthase (iNOS) is involved in mediating the toll-like receptor 4-dependent effects on the liver in the onset of fructose-induced steatosis, wild-type and iNOS knockout (iNOS(-/-)) mice were either fed tap water or 30% fructose solution for 8 weeks. Chronic consumption of 30% fructose solution led to a significant increase in hepatic steatosis and inflammation as well as plasma alanine-aminotransferase levels in wild-type mice. This effect of fructose feeding was markedly attenuated in iNOS(-/-) mice. Hepatic lipidperoxidation, concentration of phospho-IκB, nuclear factor κB activity, and tumor necrosis factor-α mRNA level were significantly increased in fructose-fed wild-type mice, whereas in livers of fructose-fed iNOS(-/-) mice, lipidperoxidation, phospho-IκB, nuclear factor κB activity, and tumor necrosis factor-α expression were almost at the level of controls. However, portal endotoxin levels and hepatic myeloid differentiation factor 88 expression were significantly higher in both fructose-fed groups compared to controls. Taken together, these data suggest that (i) the formation of reactive oxygen species in liver is a key factor in the onset of fatty liver and (ii) iNOS is involved in mediating the endotoxin/toll-like receptor 4-dependent effects in the development of fructose-induced fatty liver.

Topics: Aldehydes; Animals; Cells, Cultured; Coculture Techniques; Endotoxins; Fatty Liver; Fructokinases; Fructose; Glutathione; I-kappa B Proteins; Insulin Resistance; Kupffer Cells; Lipid Peroxidation; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; NF-kappa B; Nitric Oxide Synthase Type II; Organ Size; Toll-Like Receptor 4; Transcription, Genetic; Triglycerides; Tumor Necrosis Factor-alpha; Tyrosine; Weight Gain

Tissue accumulation of advanced glycation end products (AGEs) is associated with ageing, both in diabetics and nondiabetic subjects.. The purpose of this study was to assess immunostaining for AGEs, specifically carboxymethyl-lysine (CML) and receptor for AGEs (RAGE), in muscle tissue of healthy male subjects differing in age and weight stability.. Muscle tissue was obtained during hernia surgery in middle-aged men reporting weight maintenance (WM, n = 10) or weight gain (WG, n = 7), and also in 4 elderly men. Tissue inmunostaining for CML and RAGE was performed.. Intensity of CML and RAGE staining were highly correlated (r = 0.84) and also significantly associated with weight change and age. Muscle AGEs accretion was statistically associated with muscle expression of oxidative injury (8-hydroxy-deoxyguanosine and 4-hydroxy-2-nonenal) and inflammatory markers (tumor necrosis factor-alpha).. The increase of skeletal muscle AGEs/RAGE and markers of inflammation and oxidative injury in association with weight gain and old age suggest a pathogenic role of AGEs in weight gain and in sarcopenia of aging.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Biomarkers; Deoxyguanosine; Glycation End Products, Advanced; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Muscle, Skeletal; Oxidation-Reduction; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Tumor Necrosis Factor-alpha; Weight Gain

The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a model of hyperphagic obesity in which the animals retain the desire to run voluntarily. Running wheels were provided for 4-wk-old OLETF rats for 16 wk before they were killed 5 h (WL5), 53 h (WL53), or 173 h (WL173) after the wheels were locked. Sedentary (SED) OLETF rats that were not given access to running wheels served as age-matched cohorts. Epididymal fat pad mass, adipocyte volume, and adipocyte number were 58%, 39%, and 47% less, respectively, in WL5 than SED rats. Contrary to cessation of daily running in Fischer 344 x Brown Norway rats, epididymal fat did not increase during the first 173 h of running cessation in the OLETF runners. Serum insulin and glucose levels were 77% and 29% less, respectively, in WL5 than SED rats. Oil red O staining for intramyocellular lipid accumulation was not statistically different among groups. However, lipid peroxidation levels, as determined by total trans-4-hydroxy-2-nonenal (4-HNE) and 4-HNE normalized to oil red O, was higher in epitrochlearis muscles of SED than WL5, WL53, and WL173 rats. mRNA levels of glutathione S-transferase-alpha type 4, an enzyme involved in cellular defense against electrophilic compounds such as 4-HNE, were higher in epitrochlearis muscle of WL53 than WL173 and SED rats. In contrast, 4-HNE levels in omental fat were unaltered. Epitrochlearis muscle palmitate oxidation and relative transcript levels for peroxisome proliferator-activated receptor-delta and peroxisome proliferator-activated receptor-gamma coactivator type 1 were surprisingly not different between runners and SED rats. In summary, voluntary running was associated with lower levels of lipid peroxidation in skeletal muscle without significant changes in intramyocellular lipids or mitochondrial markers in OLETF rats at 20 wk of age. Therefore, even in a genetic animal model of extreme overeating, daily physical activity promotes improved health of skeletal muscle.

Topics: Adipose Tissue; Aging; Aldehydes; Animals; Blood Glucose; Disease Models, Animal; Eating; Glutathione Transferase; Hyperglycemia; Hyperinsulinism; Insulin; Isoenzymes; Lipid Peroxidation; Male; Mitochondria, Muscle; Muscle, Skeletal; Obesity; Oxidation-Reduction; Palmitic Acid; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Physical Exertion; PPAR gamma; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Inbred OLETF; RNA-Binding Proteins; RNA, Messenger; Running; Species Specificity; Superoxide Dismutase; Transcription Factors; Weight Gain

Weight maintenance within normal standards is recommended for prevention of conditions associated with oxidative injury. To compare oxidative damage in a post mitotic tissue, between adults differing in long-term energy balance.. During hernia surgery, a sample of skeletal muscle was obtained in 17 non-obese adults. Subjects were divided into two groups according to their self-reported weight change: weight maintainers (WM) reported <4kg increase, and weight gainers (WG) reported >5kg increment. Muscle immunohistochemistry for 8-hydroxy-deoxyguanosine (8OHdG), 4-Hydroxy-2-nonenal (4HNE), and TNF-alpha, as markers of oxidative injury and inflammation, were performed. As known positive controls for oxidative injury, we included 10 elderly subjects (66-101yr). Anthropometric measures and blood samples for clinical laboratory and serum cytokines (TNF-alpha and IL-6) were obtained.. 8OHdG was higher in WG compared with WM (149.1+/-16.2 versus 117.8+/-29.5, P=0.03), and was associated with anthropometric indicators of fat accumulation. 4HNE was similar in WG compared with WM (10.9+/-7.6 versus 9.8+/-6.3) but noticeably higher in elderly subjects (21.5+/-15.3, P=0.059). TNF-alpha protein in WG was higher compared with WM (114.0+/-41.7 versus 70.1+/-23.3, P=0.025), and was associated with weight increase.. Moderate self-reported weight increase, and body fat accumulation, suggesting long-term positive energy balance is associated with muscle DNA oxidative injury and inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Aging; Aldehydes; Case-Control Studies; Deoxyguanosine; DNA Damage; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Muscle, Skeletal; Obesity; Tumor Necrosis Factor-alpha; Weight Gain

Oxidants have been shown to be involved in alcohol-induced liver injury. This study was designed to determine whether cocoa flavonoid extract, composed mostly of epicatechin and epicatechin oligomers, protects against early alcohol-induced liver injury in rats. Male Wistar rats were fed high-fat liquid diets with or without ethanol (10-14 g/kg per day) and cocoa extract (400 mg/kg per day) continuously for 4 weeks using an enteral feeding protocol. Mean body weight gains ( approximately 4 g/day) were not significantly different between treatment groups. Cocoa extract did not affect average daily urine ethanol concentrations ( approximately 200mg/dL). After 4 weeks, serum alanine amino transferase levels of the ethanol group were increased nearly fourfold (110+/-16 IU/L) compared to control values (35+/-3 IU/L); this effect of ethanol was blocked by cocoa extract (60+/-6 IU/L). Additionally, enteral ethanol caused severe fat accumulation, mild inflammation, and necrosis in the liver; cocoa extract significantly blunted these changes. Increases in liver TNFalpha protein levels caused by ethanol were completely blocked by cocoa extract. Further, ethanol significantly increased the accumulation of protein adducts of 4-hydroxynonenal, a product of lipid peroxidation serving as an index of oxidative stress; again this was counteracted by the addition of cocoa extract. These results indicate that dietary flavanols such as those found in cocoa can prevent early alcohol-induced liver injury.

Topics: Alanine Transaminase; Aldehydes; Animals; Cacao; Catechin; Celiac Disease; Disease Models, Animal; Enteral Nutrition; Ethanol; Inflammation; Liver Diseases, Alcoholic; Necrosis; Phytotherapy; Plant Extracts; Proteins; Rats; Weight Gain