Yun-Young Cho

Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet-induced obesity

BackgroundVisceral white adipose tissue (WAT) hypertrophy, adipokine production, inflammation and fibrosis are strongly associated with obesity, but the time-course of these changes in-vivo are not fully understood. Therefore, the aim of this study was to establish the time-course of changes in adipocyte morphology, adipokines and the global transcriptional landscape in visceral WAT during the development of diet-induced obesity.ResultsC57BL/6 J mice were fed a high-fat diet (HFD) or normal diet (ND) and sacrificed at 8 time-points over 24 weeks. Excessive fat accumulation was evident in visceral WAT depots (Epidydimal, Perirenal, Retroperitoneum, Mesentery) after 2–4 weeks. Fibrillar collagen accumulation was evident in epidydimal adipocytes at 24 weeks. Plasma adipokines, leptin, resistin and adipsin, increased early and time-dependently, while adiponectin decreased late after 20 weeks. Only plasma leptin and adiponectin levels were associated with their respective mRNA levels in visceral WAT. Time-course microarrays revealed early and sustained activation of the immune transcriptome in epididymal and mesenteric depots. Up-regulated inflammatory genes included pro-inflammatory cytokines, chemokines (Tnf, Il1rn, Saa3, Emr1, Adam8, Itgam, Ccl2, 3, 4, 6, 7 and 9) and their upstream signalling pathway genes (multiple Toll-like receptors, Irf5 and Cd14). Early changes also occurred in fibrosis, extracellular matrix, collagen and cathepsin related-genes, but histological fibrosis was only visible in the later stages.ConclusionsIn diet-induced obesity, early activation of TLR-mediated inflammatory signalling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of diet-induced obesity.

Long-term adaptation of global transcription and metabolism in the liver of high-fat diet-fed C57BL/6J mice

SCOPE This study investigated the global transcriptional and metabolic changes occurring at multiple time points over 24 wk in response to a high-fat diet (HFD). METHODS AND RESULTS C57BL/6J mice were fed a HFD or normal diet (ND) over 24 wk. HFD-fed mice developed early clinical indicators of obesity-related co-morbidities including fatty liver, insulin resistance, hyperglycemia and hypercholesterolemia. Time-course microarray analysis at eight time points over 24 wk identified 332 HFD responsive genes as potential targets to counteract diet-induced obesity (DIO) and related co-morbidities. Glucose regulating enzyme activity and gene expression were altered early in the HFD-fed mice. Fatty acid (FA) and triglyceride (TG) accumulation in combination with inflammatory changes appear to be likely candidates contributing to hepatic insulin resistance. Cidea seemed to be one of representative genes related to these changes. CONCLUSION Global transcriptional and metabolic profiling across multiple time points in liver revealed potential targets for nutritional interventions to reverse DIO. In future, new approaches targeting HFD responsive genes and hepatic metabolism could help ameliorate the deleterious effects of an HFD and DIO-related complication.

Comparison of Hesperetin and Its Metabolites for Cholesterol-Lowering and Antioxidative Efficacy in Hypercholesterolemic Hamsters

This study was performed to compare the hypolipidemic and antioxidant efficacy of hesperetin and its metabolites in hypercholesterolemic hamsters. The hamsters were fed a high-fat (10% coconut oil and 0.2% cholesterol, wt/wt) diet or a high-fat diet supplemented with hesperetin (0.02%) or hesperetin metabolites, 3,4-dihydroxyphenylpropionic acid (DHPP) (0.012%) and 3-methoxy-4-hydroxycinnamic acid (ferulic acid) (0.013%), for 12 weeks. Dietary DHPP and ferulic acid were found to have significantly decreased the levels of the plasma total cholesterol, non-high-density lipoprotein-cholesterol (HDL-C), apolipoprotein B, hepatic lipids, and cholesterol-regulating enzymes compared to the control group. In particular, ferulic acid was more potent with respect to raising HDL-C/total cholesterol ratio and paraoxonase levels while decreasing atherogenic index values. Hesperetin and its metabolites seemed to enhance antioxidant capacity by lowering the hydrogen peroxide and lipid peroxide (thiobarbituric acid-reactive substrates) levels. Among the hesperetin metabolites tested, the relative potency of ferulic acid for reducing the risks of atherosclerosis in hamsters was found to be greater.

Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice

Several in vitro and in vivo studies have reported the anti-inflammatory, anti-diabetic and anti-obesity effects of the flavonoid apigenin. However, the long-term supplementary effects of low-dose apigenin on obesity are unclear. Therefore, we investigated the protective effects of apigenin against obesity and related metabolic disturbances by exploring the metabolic and transcriptional responses in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed an HFD or apigenin (0.005%, w/w)-supplemented HFD for 16 weeks. In HFD-fed mice, apigenin lowered plasma levels of free fatty acid, total cholesterol, apolipoprotein B and hepatic dysfunction markers and ameliorated hepatic steatosis and hepatomegaly, without altering food intake and adiposity. These effects were partly attributed to upregulated expression of genes regulating fatty acid oxidation, tricarboxylic acid cycle, oxidative phosphorylation, electron transport chain and cholesterol homeostasis, downregulated expression of lipolytic and lipogenic genes and decreased activities of enzymes responsible for triglyceride and cholesterol ester synthesis in the liver. Moreover, apigenin lowered plasma levels of pro-inflammatory mediators and fasting blood glucose. The anti-hyperglycemic effect of apigenin appeared to be related to decreased insulin resistance, hyperinsulinemia and hepatic gluconeogenic enzymes activities. Thus, apigenin can ameliorate HFD-induced comorbidities via metabolic and transcriptional modulations in the liver.

Actions of Ferulic Acid and Vitamin E on Prevention of Hypercholesterolemia and Atherogenic Lesion Formation in Apolipoprotein E-Deficient Mice

This study was carried out to investigate whether dietary vitamin E and ferulic acid (FA) can exert possible interactions on preventions of hypercholesterolemia and atherogenic lesion formation in C57BL/65 apolipoprotein E-deficient (apo E(-/-)) mice. Four-week-old male apo E(-/-) mice were randomly divided into three groups and given one of three types of Western diets with various amounts of vitamin E (0.02%, 0%, or 0.2%) for 15 weeks. FA was added to vitamin E-free Western diet and vitamin E-rich Western diet at the 0.02% level. The plasma total cholesterol concentration was significantly lowered when FA was added to the vitamin E-free and vitamin E-rich Western diet as compared to the normal vitamin E Western diet (0.02% vitamin E), and this was accompanied with a decreased hepatic acyl-coenzyme A:cholesterol acyltransferase activity. The hepatic and erythrocyte thiobarbituric acid-reactive substances levels were significantly lowered when FA was added to the vitamin E-rich Western diet, which was attributable to increased activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and paraoxonase. Accordingly, vitamin E and/or FA are beneficial for prevention of hypercholesterolemia and atherogenesis in apo E(-/-) mice. In particular, dietary FA exhibited an anti-atherosclerotic property, and this effect was synergistically enhanced with the vitamin E supplement.

Differential effect of corn oil-based low trans structured fat on the plasma and hepatic lipid profile in an atherogenic mouse model: comparison to hydrogenated trans fat

BackgroundTrans fat are not desirable in many aspects on health maintenance. Low trans structured fats have been reported to be relatively more safe than trans fats.MethodsWe examined the effects of low trans structured fat from corn oil (LC), compared with high trans fat shortening, on cholesterol and fatty acid metabolism in apo E deficient mice which is an atherogenic animal model. The animals were fed a high trans fat (10% fat: commercial shortening (CS)) or a low trans fat (LC) diet for 12 weeks.ResultsLC decreased apo B and hepatic cholesterol and triglyceride concentration compared to the CS group but significantly increased plasma total cholesterol and triglyceride concentration and fecal lipids with a simultaneous increase in HDL-cholesterol level, apo A-I, and the ratio of HDL-cholesterol to total cholesterol (HTR). Reduction of hepatic lipid levels by inclusion of LC intake was observed alongside modulation of hepatic enzyme activities related to cholesterol esterification, fatty acid metabolism and fecal lipids level compared to the CS group. The differential effects of LC intake on the plasma and hepatic lipid profile seemed to be partly due to the fatty acid composition of LC which contains higher MUFA, PUFA and SFA content as well as lower content of trans fatty acids compared to CS.ConclusionsWe suggest that LC may exert a dual effect on plasma and hepatic lipid metabolism in an atherogenic animal model. Accordingly, LC, supplemented at 10% in diet, had an anti-atherogenic effect on these apo E-/-mice, and increased fecal lipids, decreased hepatic steatosis, but elevated plasma lipids. Further studies are needed to verify the exact mode of action regarding the complex physiological changes and alteration in lipid metabolism caused by LC.

Low trans structured fat from flaxseed oil improves plasma and hepatic lipid metabolism in apo E―/― mice

The objective of this study was to explicate the effects of feeding low trans structured fat from flaxseed oil (LF) on plasma and hepatic lipid metabolism involved in apo E(-/-) mice. The animals were fed a commercial shortening (CS), commercial low trans fat (CL) and LF diet based on AIN-76 diet (10% fat) for 12 weeks. LF supplementation exerted a significant suppression in hepatic lipid accumulation with the concomitant decrease in liver weight. The LF significantly lowered plasma total cholesterol and free fatty acid whereas it significantly increased HDL-C concentration and the HDL-C/total-C ratio compared to the CS group. Reduction of hepatic lipid levels in the LF group was related with the suppression of hepatic enzyme activities for fatty acid and triglyceride synthesis, and cholesterol regulating enzyme activity compared to the CS and CL groups. Accordingly, low trans structured fat from flaxseed oil is highly effective for improving hyperlipidemia and hepatic lipid accumulation in apo E(-/-) mice.

Phase formation and dielectric properties of Mg2TiO4-Al2O3

Abstract Powder mixtures of end members in MgO-TiO2-Al2O3 ternary system and those of binary (1−x)Mg2TiO4-xAl2O3 were prepared corresponding to 0≤x ≤0.5 in subsolidus tie triangle of MgTiO3-Mg2TiO4-MgAl2O4 and the reaction sequence, sintering and dielectric properties of which were studied. In both cases, MgTiO3(er=17) as the second phase increased and the composition of the solid solution grains concurrently shifted toward MgAl2O4(er=8) with increasing Al2O3 content, which resulted in sluggish decrease in er. Significant difference in microstructure, however, was seen between the two methods probably due to the difference in the reaction sequences.