Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity

Obesity causes insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), but the relative contribution of sleep apnea is debatable. The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR and NAFLD in lean mice and mice with diet-induced obesity (DIO). Mice (C57BL/6J), 6-8 weeks of age were fed a high fat (n = 18) or regular (n = 16) diet for 12 weeks and then exposed to CIH or control conditions (room air) for 4 weeks. At the end of the exposure, fasting (5 h) blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and intraperitoneal glucose tolerance test (1 g/kg) were measured. In DIO mice, body weight remained stable during CIH and did not differ from control conditions. Lean mice under CIH were significantly lighter than control mice by day 28 (P = 0.002). Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index (from 1.79 ± 0.13 in control to 2.41 ± 0.26 in CIH; P = 0.05), whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index (from 10.1 ± 2.1 in control to 22.5 ± 3.6 in CIH; P < 0.01), and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice. In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity.     

Stress-induced intestinal barrier dysfunction is exacerbated during diet-induced obesity

Obesity and irritable bowel syndrome (IBS) are two major public health issues. Interestingly previous data report a marked increase of IBS prevalence in morbid obese subjects compared with non-obese subjects but underlying mechanisms remain unknown. Obesity and IBS share common intestinal pathophysiological mechanisms such as gut dysbiosis, intestinal hyperpermeability and low-grade inflammatory response. We thus aimed to evaluate the link between obesity and IBS using different animal models. Male C57Bl/6 mice received high fat diet (HFD) for 12 weeks and were then submitted to water avoidance stress (WAS). In response to WAS, HFD mice exhibited higher intestinal permeability and plasma corticosterone concentration than non-obese mice. We were not able to reproduce a similar response both in ob/ob mice and in leptin-treated non-obese mice. In addition, metformin, a hypoglycemic agent, limited fasting glycaemia both in unstressed and WAS diet-induced obese mice but only partially restored colonic permeability in unstressed HFD mice. Metformin failed to improve intestinal permeability in WAS HFD mice. Finally, cecal microbiota transplantation from HFD mice in antibiotics-treated recipient mice did not reproduce the effects observed in stressed HFD mice. In conclusion, stress induced a more marked intestinal barrier dysfunction in diet-induced obese mice compared with non-obese mice that seems to be independent of leptin, glycaemia and gut microbiota. These data should be further confirmed and the role of the dietary composition should be studied.     

Early‐life exposure to high‐fat diet influences brain health in aging mice

Epidemiological studies have suggested a link between exposure to environmental factors early in life and susceptibility to neurodegenerative diseases in adulthood. In the short term, maternal diet is important for the growth and development of the fetus; however, it may also have long‐term effects on the health status of the offspring. Here, we investigate the effect that maternal high‐fat diet during gestation has on brain health of the offspring later in life. B6129SF2/J dams were fed a high‐fat diet during the 3 weeks’ gestation, then switched to standard chow diet after delivery. Offspring were always fed regular diet for the entire study and assessed in learning, memory, and brain pathology when 18 months old. Compared with offspring from control mothers, the ones from mothers exposed to high‐fat diet had significant better performance in learning and memory tests, which associated with an amelioration of synaptic integrity. Additionally, they had a significant reduction in total tau, a decrease in its pathological conformational changes and lower levels of caspase‐3‐cleaved isoforms. Our findings demonstrate that in utero exposure to high‐fat diet plays a protective role for offspring brain health later in life. They support the novel hypothesis that targeted dietary intervention specifically restricted to the gestation period could be implemented as preventative strategy for the age‐dependent decline in brain health.     

Diet-Induced Obesity Reduces the Responsiveness of the Peripheral Taste Receptor Cells

Introduction

Obesity is a growing epidemic that causes many serious health related complications. While the causes of obesity are complex, there is conclusive evidence that overconsumption coupled with a sedentary lifestyle is the primary cause of this medical condition. Dietary consumption is controlled by appetite which is in turn regulated by multiple neuronal systems, including the taste system. However, the relationship between taste and obesity has not been well defined. Growing evidence suggests that taste perception in the brain is altered in obese animals and humans, however no studies have determined if there are altered taste responses in the peripheral taste receptor cells, which is the initiation site for the detection and perception of taste stimuli.

Methodology/Principal Findings

In this study, we used C57Bl/6 mice which readily become obese when placed on a high fat diet. After ten weeks on the high fat diet, we used calcium imaging to measure how taste-evoked calcium signals were affected in the obese mice. We found that significantly fewer taste receptor cells were responsive to some appetitive taste stimuli while the numbers of taste cells that were sensitive to aversive taste stimuli did not change. Properties of the taste-evoked calcium signals were also significantly altered in the obese mice. Behavioral analyses found that mice on the high fat diet had reduced ability to detect some taste stimuli compared to their littermate controls.

Conclusions/Significance

Our findings demonstrate that diet-induced obesity significantly influences peripheral taste receptor cell signals which likely leads to changes in the central taste system and may cause altered taste perception.     

Sex Differences in High‐fat Diet‐induced Obesity,Metabolic Alterations and Learning,and Synaptic Plasticity Deficits in Mice

Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high‐fat diet (HFD)–induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9–12 months) gained significantly more weights than the sex‐specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step‐down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open‐field and hot‐plate tests. Although, basal synaptic transmission characteristics (input–output transfer and paired‐pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long‐term potentiation (LTP) and long‐term depression (LTD)) were lower at the Schaffer collateral‐CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex‐specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity.     

Highly palatable diet consumption increases protein oxidation in rat frontal cortex and anxiety-like behavior

Obesity is frequently associated with consumption of high amounts of sugar and/or fat. Studies have demonstrated a high prevalence of overweight and obesity associated or not with increase rates of psychiatry disorders, in particular mood and anxiety disorders. Recent works have demonstrated an association between specific genes involved in oxidative stress metabolism and anxiety-like behavior. The aim of this study was to investigate the effect of a highly palatable diet enriched with sucrose in body fat mass composition, anxiety behavior and brain oxidative status. Twenty male Wistar rats received two different diets during four months: standard chow (SC) and highly palatable (HP). Metabolic parameters, behavioral tests and oxidative stress status were evaluated. Body fat mass, insulin sensitivity and glucose tolerance were altered in the HP group (p<0.01). The same group spends less time in light compartment and had a lower risk assessment behavior (p<0.05) but no differences were observed in the open field test habituation (p>0.05). Protein degradation, DCF and TBARS levels were not different in the hippocampus between groups; however, there were higher levels of protein degration in frontal cortex of HP groups (p<0.05), although DCF and TBARS levels don't differ from the SC group (p>0.05). In conclusion, our data suggest that the consumption of HP diet leads to an obese phenotype, increases protein oxidation in frontal cortex and appears to induce anxiety-like behavior in rats.     

Altered endocrine,cytokine signaling and oxidative stress: A plausible reason for differential changes in testicular cells in diet-induced and genetically-inherited – obesity in adult rats

Obesity is emerging as a potential risk factor for male infertility. It is a multifactorial disorder with primarily genetic and/or environmental factors. Our earlier studies have shown differential effects of genetically inherited-and high fat diet induced-obesity on hormones, fertility and spermatogenesis in adult male rats. In the present study, we assessed the effect of high fat diet induced – and genetically inherited – obesity on the underlying molecular mechanisms affecting spermatogenesis. The expression of hormone receptors, cytokines and markers of oxidative stress as well as cell cycle mediators were affected in both the obese groups, however, the changes were different in the two groups. This could be due to difference in fat distribution between the two types of obese groups. Altered expression of hormone receptors, cytokines, cell cycle mediators and differential effects on oxidative stress could be the plausible reason for differential changes in germ cell population in both the groups.     

Membrane lipids and ethanol tolerance in the mouse. The influence of dietary fatty acid composition

Mice of the TO Swiss strain received diets containing different amounts of saturated or unsaturated fat throughout life. These diets produced characteristic changes in cardiac phospholipid fatty acid composition, but produced no significant differences in fatty acid composition of phospholipids from a crude membrane fraction of brain. When littermates of these animals were exposed to ethanol vapour in an inhalation chamber it was observed that mice which had received a diet high in saturated fat lost the righting reflex at an estimated concentration of ethanol in blood higher than that required for mice receiving a control diet, or a diet rich in polyunsaturated fat. Analysis of the brain membrane fraction from those animals which had received ethanol revealed that mice receiving the highly saturated fat diet now had a significantly greater proportion of saturated fatty acids in brain membrane phospholipids. These results are discussed in relation to the hypothesis that brain membrane lipid composition may influence the behavioural response to ethanol.     

Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs

A diet high in fat induces cardiac hypertrophy, inflammation, and oxidative stress. Although such actions have largely been ascribed to fat deposition, the accumulation of advanced glycation end products (AGEs) and subsequent activation of the receptor for AGEs (RAGE) may also represent important mediators of cardiac injury following exposure to a Western diet. In this study, male C57BL6J and RAGE knockout mice were placed on either a standard diet (7% fat) or a Western "fast-food" diet (21% fat). Animals receiving a high-fat diet were further randomized to receive the AGE inhibitor alagebrium chloride (1 mg.kg(-1).day(-1)) and followed for 16 wk. A Western diet was associated with cardiac hypertrophy, inflammation, mitochondrial-dependent superoxide production, and cardiac AGE accumulation in wild-type mice. Although RAGE-KO mice fed a Western diet also became obese and accumulated intramyocardial lipid, cardiomyocyte hypertrophy, inflammation, and oxidative stress were attenuated compared with wild-type mice. Similarly, mice of both strains receiving alagebrium chloride had reduced levels of inflammation and oxidative stress, in association with a reduction in cardiac AGEs and RAGE. This study suggests that AGEs represent important mediators of cardiac injury associated with a Western fast-food diet. These data point to the potential utility of AGE-reducing strategies in the prevention and management of cardiac disease.     

Insulin sensitivity, fat distribution, and adipocytokine response to different diets in lean and obese cats before and after weight loss

Obesity is a major health problem in cats and a risk factor for diabetes. It has been postulated that cats are always gluconeogenic and that the rise in obesity might be related to high dietary carbohydrates. We examined the effect of a high-carbohydrate/low-protein (HC) and a high-protein/low-carbohydrate (HP) diet on glucose and fat metabolism during euglycemic hyperinsulinemic clamp, adipocytokines, and fat distribution in 12 lean and 16 obese cats before and after weight loss. Feeding diet HP led to greater heat production in lean but not in obese cats. Regardless of diet, obese cats had markedly decreased glucose effectiveness and insulin resistance, but greater suppression of nonesterified fatty acids during the euglycemic hyperinsulinemic clamp was seen in obese cats on diet HC compared with lean cats on either diet or obese cats on diet HP. In contrast to humans, obese cats had abdominal fat equally distributed subcutaneously and intra-abdominally. Weight loss normalized insulin sensitivity; however, increased nonesterified fatty acid suppression was maintained and fat loss was less in cats on diet HC. Adiponectin was negatively and leptin positively correlated with fat mass. Lean cats and cats during weight loss, but not obese cats, adapted to the varying dietary carbohydrate/protein content with changes in substrate oxidation. We conclude that diet HP is beneficial through maintenance of normal insulin sensitivity of fat metabolism in obese cats, facilitating the loss of fat during weight loss, and increasing heat production in lean cats. These data also show that insulin sensitivity of glucose and fat metabolism can be differentially regulated in cats.     

Effects of different acute hypoxic regimens on tissue oxygen profiles and metabolic outcomes

Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) during sleep. Both obesity and OSA are associated with insulin resistance and systemic inflammation, which may be attributable to tissue hypoxia. We hypothesized that a pattern of hypoxic exposure determines both oxygen profiles in peripheral tissues and systemic metabolic outcomes, and that obesity has a modifying effect. Lean and obese C57BL6 mice were exposed to 12 h of intermittent hypoxia 60 times/h (IH60) [inspired O? fraction (Fi(O?)) 21-5%, 60/h], IH 12 times/h (Fi(O?) 5% for 15 s, 12/h), sustained hypoxia (SH; Fi(O?) 10%), or normoxia while fasting. Tissue oxygen partial pressure (Pti(O?)) in liver, skeletal muscle and epididymal fat, plasma leptin, adiponectin, insulin, blood glucose, and adipose tumor necrosis factor-α (TNF-α) were measured. In lean mice, IH60 caused oxygen swings in the liver, whereas fluctuations of Pti(O?) were attenuated in muscle and abolished in fat. In obese mice, baseline liver Pti(O?) was lower than in lean mice, whereas muscle and fat Pti(O?) did not differ. During IH, Pti(O?) was similar in obese and lean mice. All hypoxic regimens caused insulin resistance. In lean mice, hypoxia significantly increased leptin, especially during SH (44-fold); IH60, but not SH, induced a 2.5- to 3-fold increase in TNF-α secretion by fat. Obesity was associated with striking increases in leptin and TNF-α, which overwhelmed effects of hypoxia. In conclusion, IH60 led to oxygen fluctuations in liver and muscle and steady hypoxia in fat. IH and SH induced insulin resistance, but inflammation was increased only by IH60 in lean mice. Obesity caused severe inflammation, which was not augmented by acute hypoxic regimens.     

低能量平衡膳食联合有氧运动对单纯性肥胖儿童体脂代谢、胰岛素抵抗及氧化应激反应的影响

摘要 目的：观察单纯性肥胖儿童经有氧运动、低能量平衡膳食联合干预后,机体体脂代谢、胰岛素抵抗及氧化应激反应的变化。方法：选择2019年8月~2021年7月期间新疆医科大学第一附属医院接收的单纯性肥胖儿童93例,将纳入的患儿根据随机数字表法分为对照组和研究组,各为46例和47例。对照组患儿接受低能量平衡膳食干预,研究组患儿接受低能量平衡膳食联合有氧运动干预。对比两组体脂代谢、胰岛素抵抗、血脂及氧化应激反应相关指标变化情况。结果：研究组干预12周后体质量指数（BMI）、甘油三酯（TG）、体脂含量、总胆固醇（TC）、体脂率、腰臀比、空腹胰岛素（FINS）、低密度脂蛋白（LDL-C）、空腹血糖（FPG）、蛋白质羰基（PC）、C肽、胰岛素抵抗指数（HONA-IR）、丙二醛（MDA）低于对照组（P<0.05）。研究组干预12周后高密度脂蛋白（HDL-C）、超氧化物歧化酶（SOD）高于对照组（P<0.05）。结论：低能量平衡膳食联合有氧运动可促进单纯性肥胖儿童体脂代谢改善,减轻胰岛素抵抗及氧化应激反应,效果确切。     

Does Long-Term High Fat Diet Always Lead to Smaller Hippocampi Volumes,Metabolite Concentrations,and Worse Learning and Memory? A Magnetic Resonance and Behavioral Study in Wistar Rats

BackgroundObesity is a worldwide epidemic with more than 600 million affected individuals. Human studies have demonstrated some alterations in brains of otherwise healthy obese individuals and elevated risk of neurodegenerative disease of old age; these studies have also pointed to slightly diminished memory and executive functions among healthy obese individuals. Similar findings were obtained in animal models of obesity induced by high fat diet. On the other hand, low carbohydrate high fat diets are currently promoted for losing weight (e.g., Atkin’s style diets). However, the long-term effects of such diets are not known. Additionally, high fat diets leading to (mild) ketonemia were shown to improve brain function in elderly humans and in some animal models.AimTo evaluate the hypothesis that long-term use of a high fat diet was associated with decreases in spatial memory, smaller hippocampi and hippocampi metabolite concentrations in Wistar rats.MethodsTwenty five male Wistar rats were put on high fat diet (HFD; 60% calories from fat, 30% from carbohydrates) on their 55^th day of life, while 25 control male rats (CONs) remained on chow. Adequate levels of essential nutrients were provided. Both groups underwent memory tests in 8-arm radial maze at 3^rd, 6^th, 9^th, and 12^th month. ¹H magnetic resonance spectroscopy was employed to measure concentrations of tNAA (marker of neuronal integrity) at one month and one year, whereas MRI was used to evaluate hippocampal volumes.ResultsObese rats (OBRs) consumed similar amount of calories as CONs, but less proteins. However, their protein intake was within recommended amounts. Throughout the experiment OBRs had statistically higher concentrations of blood ketone bodies than CONs, but still within normal values. At post-mortem assessment, OBRs had 38% larger fat deposits than CONs (p<0.05), as evaluated by volume of epididymis fat, an acknowledged marker of fat deposits in rats. Contrary to our expectations, OBRs had better scores of memory behavioral tasks than CONs throughout the experiment. At one year, their hippocampi were by 2.6% larger than in CONs (p = 0.05), whereas concentration of tNAA was 9.8% higher (p = 0.014).ConclusionLong-term HFD in our study resulted in better memory, larger hippocampal volumes, as well as higher hippocampal metabolite concentrations, possibly due to increased levels of blood ketone bodies. The results should be interpreted with caution, as results from animal models do not necessarily directly translate in human condition.     

Grape Seed and Skin Extract Prevents High-Fat Diet-Induced Brain Lipotoxicity in Rat

Obesity is related to an elevated risk of dementia and the physiologic mechanisms whereby fat adversely affects the brain are poorly understood. The present investigation analyzed the effect of a high fat diet (HFD) on brain steatosis and oxidative stress and the intracellular mediators involved in signal transduction, as well as the protection offered by grape seed and skin extract (GSSE). HFD induced ectopic deposition of cholesterol and phospholipid but not triglyceride. Moreover brain lipotoxicity is linked to an oxidative stress characterized by increased lipoperoxidation and carbonylation, inhibition of glutathione peroxidase and superoxide dismutase activities, depletion of manganese and a concomitant increase in ionizable calcium and acetylcholinesterase activity. Importantly GSSE alleviated all the deleterious effects of HFD treatment. Altogether our data indicated that HFD could find some potential application in the treatment of manganism and that GSSE should be used as a safe anti-lipotoxic agent in the prevention and treatment of fat-induced brain injury.     

MsrA Overexpression Targeted to the Mitochondria,but Not Cytosol,Preserves Insulin Sensitivity in Diet-Induced Obese Mice

There is growing evidence that oxidative stress plays an integral role in the processes by which obesity causes type 2 diabetes. We previously identified that mice lacking the protein oxidation repair enzyme methionine sulfoxide reductase A (MsrA) are particularly prone to obesity-induced insulin resistance suggesting an unrecognized role for this protein in metabolic regulation. The goals of this study were to test whether increasing the expression of MsrA in mice can protect against obesity-induced metabolic dysfunction and to elucidate the potential underlying mechanisms. Mice with increased levels of MsrA in the mitochondria (TgMito MsrA) or in the cytosol (TgCyto MsrA) were fed a high fat/high sugar diet and parameters of glucose homeostasis were monitored. Mitochondrial content, markers of mitochondrial proteostasis and mitochondrial energy utilization were assessed. TgMito MsrA, but not TgCyto MsrA, mice remain insulin sensitive after high fat feeding, though these mice are not protected from obesity. This metabolically healthy obese phenotype of TgMito MsrA mice is not associated with changes in mitochondrial number or biogenesis or with a reduction of proteostatic stress in the mitochondria. However, our data suggest that increased mitochondrial MsrA can alter metabolic homeostasis under diet-induced obesity by activating AMPK signaling, thereby defining a potential mechanism by which this genetic alteration can prevent insulin resistance without affecting obesity. Our data suggest that identification of targets that maintain and regulate the integrity of the mitochondrial proteome, particular against oxidative damage, may play essential roles in the protection against metabolic disease.     

Oxidative stress and antioxidant status in mouse kidney: effects of dietary lipid and vitamin E plus iron

The purpose of this study was to determine the effects of dietary fat, vitamin E, and iron on oxidative damage and antioxidant status in kidneys of mice. Sixty 1-month-old male Swiss-Webster mice were fed a basal vitamin E-deficient diet that contained either 8% fish oil + 2% corn oil or 10% lard with or without 1 g all-rac-alpha-tocopherol acetate or 0.74 g ferric citrate per kilogram of diet for 4 weeks. Significantly (P < 0.05) higher levels of lipid peroxidation products, thiobarbituric acid reactants (TBAR), and conjugated dienes were found in the kidneys of mice fed with fish oil compared with mice fed lard irrespective of vitamin E status. Mice maintained on a vitamin E-deficient diet had significantly higher renal levels of TBAR, but not conjugated dienes, than the supplemented group. Fish oil fed mice receiving vitamin E supplementation had lower levels of alpha-tocopherol than did mice in the lard fed group. Significantly higher levels of ascorbic acid were also found in the kidneys of mice fed with fish oil than were found in mice fed lard. The levels of protein carbonyls and glutathione (GSH), and activities of catalase, superoxide dismutase, selenium (Se)-GSH peroxidase, and non-Se-GSH peroxidase were not significantly altered by dietary fat or vitamin E. Dietary iron had no significant effect on any of the oxidative stress and antioxidant indices measured. The results obtained provide experimental evidence for the pro-oxidant effect of high fish oil intake in mouse kidney and suggest that dietary lipids play a key role in determining cellular susceptibility to oxidative stress.     

Diet-induced elevations in serum cholesterol are associated with alterations in hippocampal lipid metabolism and increased oxidative stress

The structure and function of the hippocampus, a brain region critical for learning and memory, is impaired by obesity and hyperlipidemia. Peripheral cholesterol and sphingolipids increase progressively with aging and are associated with a range of age-related diseases. However, the mechanisms linking peripheral cholesterol metabolism to hippocampal neuroplasticity remain poorly understood. To determine whether diets that elevate serum cholesterol influence lipid metabolism in the hippocampus, we maintained rats on a diet with high amounts of saturated fat and simple sugars for 3 months and then analyzed hippocampal lipid species using tandem mass spectrometry. The high fat diet was associated with increased serum and liver cholesterol and triglyceride levels, and also promoted cholesterol accumulation in the hippocampus. Increases in hippocampal cholesterol were associated with elevated galactosyl ceramide and sphingomyelin. To determine whether changes in lipid composition exerted biological effects, we measured levels of the lipid peroxidation products 4-hydroxynonenal-lysine and 4-hydroxynonenal-histidine; both were increased locally in the hippocampus, indicative of cell membrane-associated oxidative stress. Taken together, these observations support the existence of a potentially pathogenic relationship between dietary fat intake, peripheral cholesterol and triglyceride levels, brain cell sphingolipid metabolism, and oxidative stress.     

Oxidative Stress-Dependent Coronary Endothelial Dysfunction in Obese Mice

Obesity is involved in several cardiovascular diseases including coronary artery disease and endothelial dysfunction. Endothelial Endothelium vasodilator and vasoconstrictor agonists play a key role in regulation of vascular tone. In this study, we evaluated coronary vascular response in an 8 weeks diet-induced obese C57BL/6 mice model. Coronary perfusion pressure in response to acetylcholine in isolated hearts from obese mice showed increased vasoconstriction and reduced vasodilation responses compared with control mice. Vascular nitric oxide assessed in situ with DAF-2 DA showed diminished levels in coronary arteries from obese mice in both basal and acetylcholine-stimulated conditions. Also, released prostacyclin was decreased in heart perfusates from obese mice, along with plasma tetrahydrobiopterin level and endothelium nitric oxide synthase dimer/monomer ratio. Obesity increased thromboxane A₂ synthesis and oxidative stress evaluated by superoxide and peroxynitrite levels, compared with control mice. Obese mice treated with apocynin, a NADPH oxidase inhibitor, reversed all parameters to normal levels. These results suggest that after 8 weeks on a high-fat diet, the increase in oxidative stress lead to imbalance in vasoactive substances and consequently to endothelial dysfunction in coronary arteries.     

Time-restricted feeding prevents high-fat and high-cholesterol diet-induced obesity but fails to ameliorate atherosclerosis in apolipoprotein E-knockout mice

One of the leading risk factors for atherosclerosis is obesity, which is commonly caused by a nutrient-rich Western-style diet, sedentary behaviors, and shift work. Time-restricted (TR) feeding and intermittent fasting are both known to prevent overweight and adiposity, improve glucose tolerance, and decrease plasma cholesterol in high-fat diet-induced obese mice. Here we examined the overall effects of TR feeding of a Western diet (fat, 40.5 Kcal%; cholesterol, 0.21 g%) using 8-week-old Apoe^−/− mice. Mice were assigned into three groups: (1) an ad libitum (AL) group fed an AL Western diet, (2) a TR group with restricted access to a Western diet (15 h/day, 12:00 to 3:00 Zeitgeber time [ZT]); and (3) an Ex/TR group fed a TR Western diet and subjected to physical exercise at 12:00 ZT. Mice in the AL group gained body weight rapidly during the 14-week observation period. With TR feeding, excessive weight gain, liver adiposity, visceral fat, and brown adipose tissue volume were effectively suppressed. Although TR feeding failed to decrease Oil Red O-stained aortic plaques in Apoe^−/− mice, physical exercise significantly decreased them. Neither TR feeding with exercise nor that without exercise decreased the mean area under the curve of the plasma cholesterol level or the fasting plasma glucose. Collectively, TR feeding of a Western diet prevented the development of obesity but failed to ameliorate atherosclerosis in Apoe^−/− mice.