Oxidative stress and inflammatory mediators contribute to endothelial dysfunction in high-fat diet-induced obesity in mice

Objective We investigated the effects of high-fat diet-induced obesity on vascular proinflammatory factors and oxidative stress on endothelium-dependent relaxation of the aorta. Methods Female Swiss mice were submitted to a high-fat diet for 16 weeks. At the end of the experimental period, we evaluated blood pressure, relaxation in response to acetylcholine in aortic rings in the absence and the presence of the superoxide anion scavenger, superoxide dismutase (SOD, 150 U/ml), and the nuclear factor (NF)-kappa B inhibitor, sodium salicylate (5 mmol/l). Aortic protein expression of endothelial nitric oxide synthase, Cu/Zn-SOD, NF-kappa B, I kappa B-alpha, and proinflammatory cytokines were also evaluated. Results Obese mice presented higher systolic and diastolic blood pressure than control mice (P<0.05). The relaxation of aortas to acetylcholine, but not to sodium nitroprusside, was significantly decreased in obese mice and was corrected by both SOD and sodium salicylate (P<0.05). The protein expression of endothelial nitric oxide synthase and Cu/Zn-SOD was significantly decreased in aorta from obese mice (P<0.05). Total p65 NF-kappa B subunit protein expression was not affected by obesity, but the protein expression of NF-kappa B inhibitor I kappa B-alpha was lower in aorta from obese mice (P<0.05). There were no significant differences in the interleukin (IL)-1 beta and IL-6 protein expression between groups. In contrast, the expression of TNF-alpha was significantly increased in aortas from obese mice. Conclusion Our resultssuggest that the reducedantioxidant defense and the local NF-kappa B pathway play an important role in the impairment of endothelium-dependent relaxation in aorta from obese mice. J Hypertens 28: 2111-2119 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Obesity induced by high-fat diet promotes insulin resistance in the ovary

Besides the effects on peripheral energy homeostasis, insulin also has an important role in ovarian function. Obesity has a negative effect on fertility, and may play a role in the development of the polycystic ovary syndrome in susceptible women. Since insulin resistance in the ovary could contribute to the impairment of reproductive function in obese women, we evaluated insulin signaling in the ovary of high-fat diet-induced obese rats. Female Wistar rats were submitted to a high-fat diet for 120 or 180 days, and the insulin signaling pathway in the ovary was evaluated by immunoprecipitation and immunoblotting. At the end of the diet period, we observed insulin resistance, hyperinsulinemia, an increase in progesterone serum levels, an extended estrus cycle, and altered ovarian morphology in obese female rats. Moreover, in female obese rats treated for 120 days with the high-fat diet, the increase in progesterone levels occurred together with enhancement of LH levels. The ovary from high-fat-fed female rats showed a reduction in the insulin receptor substrate/phosphatidylinositol 3-kinase/AKT intracellular pathway, associated with an increase in FOXO3a, IL1B, and TNF alpha protein expression. These changes in the insulin signaling pathway may have a role in the infertile state associated with obesity. Journal of Endocrinology (2010) 206, 65-74

Effects of a high fat diet on liver mitochondria: increased ATP-sensitive K(+) channel activity and reactive oxygen species generation

High fat diets are extensively associated with health complications within the spectrum of the metabolic syndrome. Some of the most prevalent of these pathologies, often observed early in the development of high-fat dietary complications, are non-alcoholic fatty liver diseases. Mitochondrial bioenergetics and redox state changes are also widely associated with alterations within the metabolic syndrome. We investigated the mitochondrial effects of a high fat diet leading to non-alcoholic fatty liver disease in mice. We found that the diet does not substantially alter respiratory rates, ADP/O ratios or membrane potentials of isolated liver mitochondria. However, H(2)O(2) release using different substrates and ATP-sensitive K(+) transport activities are increased in mitochondria from animals on high fat diets. The increase in H(2)O(2) release rates was observed with different respiratory substrates and was not altered by modulators of mitochondrial ATP-sensitive K(+) channels, indicating it was not related to an observed increase in K(+) transport. Altogether, we demonstrate that mitochondria from animals with diet-induced steatosis do not present significant bioenergetic changes, but display altered ion transport and increased oxidant generation. This is the first evidence, to our knowledge, that ATP-sensitive K(+) transport in mitochondria can be modulated by diet.

A short-term, high-fat diet up-regulates lipid metabolism and gene expression in human skeletal muscle

Background: Dietary fatty acids may be important in regulating gene expression. However, little is known about the effect of changes in dietary fatty acids on gene regulation in human skeletal muscle.
Objective: The objective was to determine the effect of altered dietary fat intake on the expression of genes encoding proteins necessary for fatty acid transport and &szlig;-oxidation in skeletal muscle.
Design: Fourteen well-trained male cyclists and triathletes with a mean (&plusmn; SE) age of 26.9 &plusmn; 1.7 y, weight of 73.7 &plusmn; 1.7 kg, and peak oxygen uptake of 67.0 &plusmn; 1.3 mL &dot; kg-1 &dot; min-1 consumed either a high-fat diet (HFat: > 65% of energy as lipids) or an isoenergetic high-carbohydrate diet (HCho: 70–75% of energy as carbohydrate) for 5 d in a crossover design. On day 1 (baseline) and again after 5 d of dietary intervention, resting muscle and blood samples were taken. Muscle samples were analyzed for gene expression [fatty acid translocase (FAT/CD36), plasma membrane fatty acid binding protein (FABPpm), carnitine palmitoyltransferase I (CPT I), &szlig;-hydroxyacyl-CoA dehydrogenase (&szlig;-HAD), and uncoupling protein 3 (UCP3)] and concentrations of the proteins FAT/CD36 and FABPpm.
Results: The gene expression of FAT/CD36 and &szlig; -HAD and the gene abundance of FAT/CD36 were greater after the HFat than after the HCho diet (P < 0.05). Messenger RNA expression of FABPpm, CPT I, and UCP-3 did not change significantly with either diet.
Conclusions: A rapid and marked capacity for changes in dietary fatty acid availability to modulate the expression of mRNA-encoding proteins is necessary for fatty acid transport and oxidative metabolism. This finding is evidence of nutrient-gene interactions in human skeletal muscle.

Casitas b-lineage lymphoma-deficient mice are pretected against high-fat diet-induuced obesity and insulin resistance

Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity involved in regulating the degradation of receptor tyrosine kinases. We have recently reported that c-Cbl^–/– mice exhibit a lean phenotype and enhanced peripheral insulin action likely due to elevated energy expenditure. In the study reported here, we examined the effect of a high-fat diet on energy homeostasis and glucose metabolism in these animals. When c-Cbl^–/– mice were fed a high-fat diet for 4 weeks, they maintained hyperphagia, higher whole-body oxygen consumption (27%), and greater activity (threefold) compared with wild-type animals fed the same diet. In addition, the activity of several enzymes involved in mitochondrial fat oxidation and the phosphorylation of acetyl CoA carboxylase was significantly increased in muscle of high-fat–fed c-Cbl–deficient mice, indicating a greater capacity for fat oxidation in these animals. As a result of these differences, fat-fed c-Cbl^–/– mice were 30% leaner than wild-type animals and were protected against high-fat diet–induced insulin resistance. These studies are consistent with a role for c-Cbl in regulating nutrient partitioning in skeletal muscle and emphasize the potential of c-Cbl as a therapeutic target in the treatment of obesity and type 2 diabetes.

Adaptations to short-term high-fat diet persist during exercise despite high carbohydrate availability

Purpose: Five days of a high-fat diet produce metabolic adaptations that increase the rate of fat oxidation during prolonged exercise. We investigated whether enhanced rates of fat oxidation during submaximal exercise after 5 d of a high-fat diet would persist in the face of increased carbohydrate (CHO) availability before and during exercise.


Methods: Eight well-trained subjects consumed either a high-CHO (9.3 g·kg-1·d-1 CHO, 1.1 g·kg-1·d-1 fat; HCHO) or an isoenergetic high-fat diet (2.5 g·kg-1·d-1 CHO, 4.3 g·kg-1·d-1 fat; FAT-adapt) for 5 d followed by a high-CHO diet and rest on day 6. On day 7, performance testing (2 h steady-state (SS) cycling at 70% peak O2 uptake [[latin capital V with dot above]O2peak] + time trial [TT]) of 7 kJ·kg-1) was undertaken after a CHO breakfast (CHO 2 g·kg-1) and intake of CHO during cycling (0.8 g·kg-1·h-1).


Results: FAT-adapt reduced respiratory exchange ratio (RER) values before and during cycling at 70% [latin capital V with dot above]O2peak; RER was restored by 1 d CHO and CHO intake during cycling (0.90 ± 0.01, 0.80 ± 0.01, 0.91 ± 0.01, for days 1, 6, and 7, respectively). RER values were higher with HCHO (0.90 ± 0.01, 0.88 ± 0.01 (HCHO > FAT-adapt, P < 0.05), 0.95 ± 0.01 (HCHO > FAT-adapt, P < 0.05)). On day 7, fat oxidation remained elevated (73 ± 4 g vs 45 ± 3 g, P < 0.05), whereas CHO oxidation was reduced (354 ± 11 g vs 419 ± 13 g, P < 0.05) throughout SS in FAT-adapt versus HCHO. TT performance was similar for both trials (25.53 ± 0.67 min vs 25.45 ± 0.96 min, NS).


Conclusion: Adaptations to a short-term high-fat diet persisted in the face of high CHO availability before and during exercise, but failed to confer a performance advantage during a TT lasting ~ 25 min undertaken after 2 h of submaximal cycling.

Increased probiotic yogurt or resistant starch intake does not affect isoflavone bioavailability in subjects consuming a high soy diet

Objective - Probiotics and prebiotics that affect gut microflora balance and its associated enzyme activity may contribute to interindividual variation in isoflavone absorption after soy intake, possibly enhancing isoflavone bioavailability. This study examined the effects of the consumption of bioactive yogurt (a probiotic) or resistant starch (a known prebiotic) in combination with high soy intake on soy isoflavone bioavailability.

Methods - Using a crossover design, chronic soy consumption was compared with soy plus probiotic yogurt or resistant starch in older male and postmenopausal females (n = 31). Isoflavone bioavailability was assessed at the beginning and end of each 5-wk dietary period by sampling plasma and urine after a standardized soy meal.

Results - Chronic soy intake did not significantly affect plasma or urinary isoflavones after the soy meal and there were no significant effects of probiotic or resistant starch treatment. However, there were trends for increased circulating plasma daidzein and genistein after the probiotic treatment and for increased plasma daidzein and genistein 24 h after soy intake with resistant starch treatment. Neither treatment induced or increased equol production, although there was a trend for increased plasma equol in “equol-positive” subjects (n = 12) after probiotic treatment.

Conclusion - The weak or absence of effects of probiotic yogurt or resistant starch supplement to a chronic soy diet suggests that gut microflora were not modified in a manner that significantly affected isoflavone bioavailability or metabolism.

Green tea, black tea, and epigallocatechin modify body composition, improve glucose tolerance, and differentially alter metabolic gene expression in rats fed a high-fat diet

The mechanisms of how tea and epigallocatechin-3-gallate (EGCG) lower body fat are not completely understood. This study investigated long-term administration of green tea (GT), black tea (BT), or isolated EGCG (1 mg/kg per day) on body composition, glucose tolerance, and gene expression related to energy metabolism and lipid homeostasis; it was hypothesized that all treatments would improve the indicators of metabolic syndrome. Rats were fed a 15% fat diet for 6 months from 4 weeks of age and were supplied GT, BT, EGCG, or water. GT and BT reduced body fat, whereas GT and EGCG increased lean mass. At 16 weeks GT, BT, and EGCG improved glucose tolerance. In the liver, GT and BT increased the expression of genes involved in fatty acid synthesis (SREBP-1c, FAS, MCD, ACC) and oxidation (PPAR-α, CPT-1, ACO); however, EGCG had no effect. In perirenal fat, genes that mediate adipocyte differentiation were suppressed by GT (Pref-1, C/EBP-β, and PPAR-γ) and BT (C/EBP-β), while decreasing LPL, HSL, and UCP-2 expression; EGCG increased expression of UCP-2 and PPAR-γ genes. Liver triacylglycerol content was unchanged. The results suggest that GT and BT suppressed adipocyte differentiation and fatty acid uptake into adipose tissue, while increasing fat synthesis and oxidation by the liver, without inducing hepatic fat accumulation. In contrast, EGCG increased markers of thermogenesis and differentiation in adipose tissue, while having no effect on liver or muscle tissues at this dose. These results show novel and separate mechanisms by which tea and EGCG may improve glucose tolerance and support a role for these compounds in obesity prevention.

Novel high salt content polymer electrolytes based on high Tg polymers

Conductivities greater than or equal to 10⁻⁸ S cm⁻¹ at T_g are reported in polymer electrolytes based on lithium triflate salt and a series of polymers whose T_g is greater than 90°C. The highest conductivities were observed for poly(acrylonitrile) based systems with salt concentrations greater than 60 wt.%. The conductivity in all cases investigated increases with increasing salt concentration. ¹H-NMR T₂ relaxation measurements suggest that T_g decreases with increasing salt content and confirms that these materials are glassy at room temperature and hence that the conductivity is significantly decoupled from the structural relaxations. It appears that the nature of the polymer is important in determining the level of ionic conductivity, possibly due to differences in polymer coordinating ability or differences in T_g. Polymer-in-salt mixtures based on a tetra-alkyl ammonium imide molten salt and several high T_g polymers are also reported. The conductivities of these mixtures appear to be independent of the polymer type.

Diet high in monounsaturated fat does not have a different effect on arterial elasticity than a low-fat, high-carbohydrate diet

Objective : To compare the effects of a modified-fat diet high in monounsaturated fat, and a low-fat/high-carbohydrate diet on arterial elasticity.
Design : Randomized crossover design; each diet period was 1 month and a 2-week wash out period occurred in between.
Subjects/setting : Thirty healthy, free-living, nonsmoking men and women were recruited from the Melbourne, Australia, metropolitan region of Australia. Men were aged 35 to 55 years and postmenopausal women were aged 50 to 60 years and were not taking hormone replacement therapy. Twenty-eight subjects completed the study.
Intervention : Two diets of equal energy value: a modified-fat diet and a low-fat/high-carbohydrate diet; the modified-fat diet had 3 times more energy from monounsaturated fat.
Main outcome measures : Arterial elasticity and serum lipoprotein concentrations.
Statistical analysis : The general linear model was used to investigate overall effect and any carryover or order effects. Paired t test and the general linear model were used to compare the results from the 2 diet periods.
Results : High-density lipoprotein cholesterol concentration was significantly higher on the modified-fat diet than on the low-fat/low-carbohydrate diet. Arterial elasticity and concentrations of total cholesterol, low-density lipoprotein cholesterol, and triglycerides were not significantly different on the 2 diets.
Applications/conclusions : There is no evidence to favor a diet high in monounsaturated fat over a low-fat/high-carbohydrate diet because of an effect on arterial elasticity. Other changes in diet may be needed to cause a beneficial effect on arterial elasticity.

The use of table and cooking salt in a sample of Australian adults

Dietary sodium, the major source being salt, is associated with hypertension. Australian adults consume more than the recommended amount of salt and approximately 15% of dietary sodium comes from salt added at the table and during cooking. Objective: To determine the frequency of and the demographic characteristics associated with discretionary salt use. Design: A cross sectional survey conducted in shopping centres within Metropolitan Melbourne. Participants completed a questionnaire assessing discretionary salt use and attitudes to salt intake. Outcomes: Four hundred and seventy four surveys were collected (65% female, 77% Caucasian, 64% holding a university qualification). Eighty nine percent of respondents were classified as salt users and 11% as non-salt users. Of the salt users 52% reported that they always or sometimes add salt during cooking and at the table. Those of Asian descent and younger respondents aged 18-24 years were more likely to be salt users (chi2=12.3, df=2, p<0.001; chi2=19.2, df=5, p<0.01). Conclusion: Discretionary salt use remains high. To successfully reduce population dietary salt intake public health campaigns are urgently required and need to include consumer advice to reduce discretionary salt use, whilst reducing the salt added to processed foods. Such campaigns should include younger age groups and should be appropriate for all ethnic backgrounds to raise the awareness of the risks of a high salt diet on health.

Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6J mice maintained on a high fat diet

The renin–angiotensin system (RAS) is functional within adipose tissue and angiotensin II, the active component of RAS, has been implicated in adipose tissue hypertrophy and insulin resistance. In this study, captopril, an angiotensin converting enzyme (ACE) inhibitor that prevents angiotensin II formation, was used to study the development of diet-induced obesity and insulin resistance in obesity prone C57BL/6J mice. The mice were fed a high fat diet (w/w 21% fat) and allowed access to either water or water with captopril added (0.2 mg/ml). Body weight was recorded weekly and water and food intake daily. Glucose tolerance was determined after 11–12 weeks. On completion of the study (after 16 weeks of treatment), the mice were killed and kidney, liver, epididymal fat and extensor digitorum longus muscle (EDL) were weighed. Blood samples were collected and plasma analysed for metabolites and hormones. Captopril treatment decreased body weight in the first 2 weeks of treatment. Food intake of captopril-treated mice was similar to control mice prior to weight loss and was decreased after weight loss. Glucose tolerance was improved in captopril-treated mice. Captopril-treated mice had less epididymal fat than control mice. Relative to body weight, captopril-treated mice had increased EDL weight. Relative to control mice, mice administered captopril had a higher plasma concentration of adiponectin and lower concentrations of leptin and non-esterified fatty acids (NEFA). The results indicate that captopril both induced weight loss and improved insulin sensitivity. Thus, captopril may eventually be used for the treatment of obesity and Type 2 diabetes.

Elevated levels of triglyceride and triglyceride-rich lipoprotein triglyceride induced by a high-carbohydrate diet is associated with polymorphisms of AP0A5-1131T>C and AP0C3-482C> in chinese healthy young adults

Background/aims: Changes in lipid profiles have been shown to be associated with diet and apolipoprotein (APO) polymorphisms. Therefore, 2 polymorphisms, i.e. APOA5-1131T>C and APOC3-482C>T, and serum lipids were examined in a Chinese healthy young population with high-carbohydrate/low-fat (HC/LF) diet intervention.

Methods: After a wash-out diet for 7 days, 56 young adults (22.89 +/- 1.80 years) received the HC/LF diet for 6 days. Body mass index (BMI) and fasting serum lipid profiles at baseline, after the wash-out diet, and after the HC/LF diet were measured.

Results: APOA5-1131C carriers had higher triglyceride (TG) and TG-rich lipoprotein TG (TRL-TG) levels at baseline and after the HC/LF diet, though this mainly corresponded to the female cohort. APOC3-482T carriers had higher TRL-TG levels following the wash-out and HC/LF diets, but these were not directly attributable to a single gender.

Conclusions: Both polymorphisms may play an important role in the elevated TG and TRL-TG levels induced by the HC/LF diet, especially in females, thus indicating a potential dietary prevention of coronary heart disease in this Chinese cohort.

Associations of the SREBP-1c gene polymorphism with gender-specific changes in serum lipids induced by a high-carbohydrate diet in healthy Chinese youth

We investigated the possible association between the sterol regulatory element-binding protein-1c gene (SREBP-1c) rs2297508 polymorphism and the changes in lipid profiles in a high-carbohydrate and low-fat (high-CHO/LF) diet in a Chinese population well characterized by a lower incidence of coronary heart disease and a diet featuring higher carbohydrate and lower fat. Fifty-six healthy youth (aged 22.89 ± 1.80 years) were given wash-out diets of 31% fat and 54% carbohydrate for 7 days, followed by the high-CHO/LF diet of 15% fat and 70% carbohydrate for 6 days, without total energy restriction. Fasting blood samples were collected. Serum variables of lipid and glucose metabolism after the wash-out and high-CHO/LF diets, as well as the rs2297508 polymorphism, were analyzed. Compared with the male subjects on the wash-out diet, significantly elevated levels of high-density lipoprotein cholesterol (HDL-C) and decreased levels of apolipoprotein B-100 were observed in the male carriers of the C allele after the high-CHO/LF diet. In the female subjects, significantly increased triacylglycerol levels, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were found in the GG genotype after the high-CHO/LF diet. These results suggest that the C allele of the rs2297508 polymorphism is associated with a retardation of the increases in serum triacylglycerol, serum insulin, and HOMA-IR in females and with the elevated serum HDL-C in males after the high-CHO/LF diet.