Dose-Response Evaluation of Scopoletin, a Phytochemical, in a High-Fructose High-Fat Diet-Induced Dyslipidemia Model in Wistar Rats.

The putative hypolipidemic properties of scopoletin have not been fully confirmed due to a lack of validation in an irreversible chronic hyperlipidemia animal model. The druggability also needs to be studied in terms of bioavailability in the vascular compartment. Accordingly, we conducted a study to assess the hypolipidemic and pharmacokinetic behavior of scopoletin in the high-fructose high-fat diet (HFHFD)-induced dyslipidemia model in Wistar rats. A total of 42 rats were studied, with 6 in each of the 7 groups. A 60-day HFHFD opted for induction of dyslipidemia. Group I and groups II-VII received normal rat chow diet and HFHFD, respectively. Oral scopoletin (1, 5, 10 mg/kg) and atorvastatin 5 mg/kg were administered in groups III-VI, respectively, once daily for the next 15 days. A separate group, group VII, was used for the pharmacokinetic assessment comparing the scopoletin 10 mg/kg intraperitoneally (IP) in group VII versus the oral (group V). Pharmacokinetic blood sampling was performed on the 10th day of continuous once-daily therapy. Rats were sacrificed for the histological examination. All three scopoletin dosages significantly decreased the total cholesterol, low-density lipoproteins, and triglycerides (P < .05 for all), but not in a dose-dependent manner. Atherogenic Index of plasma, Castelli's risk indices, and histopathological findings confirmed the protective effect of scopoletin. The IP administration showed a 23.18% higher exposure than the oral route (P < .001 for area under the curve and P < .05 for concentration-maximum). This study confirms the hypolipidemic efficacy of scopoletin in a more robust irreversible model of dyslipidemia. Scopoletin's gut absorption in the disease state may also boost the initial phase exploratory clinical trial.

Scopoletin Improves Glucose Homeostasis in the High-Fructose High-Fat Diet-Induced Diabetes Model in Wistar Rats.

Antihyperglycemic action of scopoletin needs to be validated before considering it for clinical trials. The present study explored antihyperglycemic action of scopoletin in high-fructose high-fat diet (HFHFD)-induced diabetes in rats. The animal study was performed using 48 rats, 6 in each group. HFHFD was administered for model induction for 74 days. Rats in Group I (normal control [NC]) and group II (experimental control [EC]) received normal saline and HFHFD, respectively, throughout the study. Groups III, IV, V, and VI received oral scopoletin (1 mg/kg [low dose, LD], 5 mg/kg [medium dose, MD], 10 mg/kg [high dose, HD]), and metformin (250 mg/kg; positive control [PC] for efficacy), respectively, once daily from day 60 to 74, in addition to HFHFD. Group VII (10 mg/kg oral scopoletin safety group) and VIII (0.1 mg/kg oral warfarin; PC for safety) were separately used for bleeding time-clotting time (BTCT) assessment on days 60, 68, and 74. Groups I, VII, and VIII rats were studied for safety assessment. Later, animals were sacrificed for histological examination. Scopoletin-treated groups showed a significant decline in glucose levels, especially in the MD (5.18 ± 0.12) and HD group (5.271 ± 0.11) in comparison to the EC (6.37 ± 0.05) on day 74 (P < .05). Two weeks after scopoletin treatment, ß-cell function significantly improved (53.073 ± 4.67) in the MD group versus 29.323 ± 8.505 in the NC group (P < .05). A statistically significant difference was observed when the MD group (53.07 ± 4.67) was compared to the metformin-treated group (24.80 ± 3.24; P < .05). The safety assessment in the form of BTCT findings did not observe a difference among groups I, VII, and VIII (P > .05). The study showed that scopoletin dose-independently reversed insulin resistance. Consequently, scopoletin can be a potential candidate for antidiabetic drug development.

Effects of chronic mirabegron treatment on metabolic and cardiovascular parameters as well as on atherosclerotic lesions of WHHL rabbits with high-fructose high-fat diet-induced insulin resistance.

BACKGROUND AND AIM: Metabolic syndrome (MetS) is a global health and economic burden. Finding a suitable pharmacological approach for managing this syndrome is crucial. We explored the therapeutic potential of mirabegron (MIR), a ß3-adrenergic receptor agonist, as a repurposed agent for the treatment of MetS and its cardiovascular consequences. METHODS: Thirty Watanabe heritable hyperlipidemic rabbits (WHHL) were divided into 3 groups: control, high-fructose high-fat diet (HFFD) and HFFD + MIR that received a chow diet, HFFD and HFFD along with MIR treatment, respectively. The protocol lasted for 12 weeks, during which weight and abdominal circumference were monitored; plasma fasting levels of lipids, glucose and insulin were measured and an intravenous glucose tolerance test (IVGTT) was performed. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Cardiac function was assessed using in-vivo and ex-vivo approaches. Vascular reactivity was estimated via isolated carotid arteries method. Aortic atherosclerosis was evaluated using histological and immuno-histochemical techniques. RESULTS: In contrast to the HFFD group, MIR-treated rabbits showed fasting insulin, HOMA-IR and TG levels stabilization and exhibited improved cardiac inotropy and lusitropy, while on the other hand, displayed aggravated atheroma plaque development. CONCLUSION: Long-term treatment with MIR prevented the increase in TG levels and the establishment of IR and enhanced the cardiac function of a rabbit animal model of MetS with combined dyslipidemia and IR.

Effect of Oral Administration of Weissella confusa on Fecal and Plasma Ethanol Concentrations, Lipids and Glucose Metabolism in Wistar Rats Fed High Fructose and Fat Diet.

BACKGROUND AND PURPOSE: In previous investigations, Weissella confusa was shown to lack the metabolic pathway from fructose to mannitol and to produce ethanol when cultivated in the presence of fructose. Hence, we assessed the effect of oral administration of W. confusa (strain NRRL-B-14171) on blood and fecal ethanol concentrations, glucose and lipid metabolism and traits of the metabolic syndrome in Wistar rats (n=27) fed diets with two different fat and fructose levels and with or without the addition of W. confusa during a total intervention time of 15 weeks (105 days). MATERIALS AND METHODS: From week 1 to 6, rats were given a medium fructose and fat (MFru-MF) diet containing 28% fructose and 10% fat without the addition of W. confusa (control group, n=13) or mixed with 30 g per kg diet of lyophilized W. confusa (10.56 ± 0.20 log CFU/g; W. confusa group, n=14). From week 7 to 15, the percentage of dietary fructose and fat in the control and W. confusa group was increased to 56% and 16%, respectively (high fructose-high fat (HFru-HF) diet). RESULTS: In HFru-HF-fed rats, W. confusa was detected in feces, regardless of whether W. confusa was added to the diet or not, but not in rats receiving the MFru-MF diet without added W. confusa or in an additional control group (n=10) fed standard rat food without fructose, increased fat content and W. confusa. This indicates that fecal W. confusa may be derived from orally administered W. confusa as well as - in the case of high fructose and fat intake and obesity of rats - from the intestinal microbiota. As shown by multifactorial ANOVA, blood ethanol, the relative liver weight, serum triglycerides, and serum cholesterol as well as fecal ethanol, ADH, acetate, propionate and butyrate, but not lactate, were significantly higher in the W. confusa - compared to the control group. DISCUSSION: This is the first in vivo trial demonstrating that heterofermentative lactic acid bacteria lacking the mannitol pathway (like W. confusa) can increase fecal and blood ethanol concentrations in mammals on a high fructose-high fat diet. This may explain why W. confusa resulted in hyperlipidemia and may promote development of NAFLD in the host.

Effect of omega-3 fatty acids on glucose homeostasis: role of free fatty acid receptor 1.

Insulin resistance is a worldwide health problem. This study investigated the acute effects of eicosapentanoic acid (EPA) on glucose homeostasis focusing on the role of free fatty acid receptor 1 (FFAR1) and the chronic effects of fish oil omega-3 fatty acids on insulin resistance. Insulin resistance was induced by feeding mice high-fructose, high-fat diet (HFrHFD) for 16 weeks. In the first part, the acute effects of EPA alone and in combination with GW1100 and DC260126 (FFAR1 blockers) on glucose homeostasis and hepatic phosphatidyl-inositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) were investigated in standard chow diet (SCD)- and HFrHFD-fed mice. In the second part, mice were treated with fish oil omega-3 fatty acids for 4 weeks starting at the week 13 of feeding HFrHFD. Changes in the blood- and liver tissue-insulin resistance markers and FFAR1 downstream signals were recorded at the end of experiment. Results showed that EPA increased 0 and 30 min blood glucose levels after glucose load in SCD-fed mice but improved glucose tolerance in HFrHFD-fed mice. Moreover, FFAR1 blockers reduced EPA effects on glucose tolerance and hepatic PIP2 and DAG levels. On the other hand, chronic use of fish oil omega-3 fatty acids increased FBG levels and decreased serum insulin and triglycerides levels without improving the index of insulin resistance. Also, they increased hepatic ß-arrestin-2, PIP2, and pS473 Akt levels but decreased DAG levels. In conclusion, EPA acutely improved glucose homeostasis in HFrHFD-fed mice by modulating the activity of FFAR1. However, the chronic use of fish oil omega-3 fatty acids did not improve the insulin resistance.

High Oleic Acid Peanut Oil and Extra Virgin Olive Oil Supplementation Attenuate Metabolic Syndrome in Rats by Modulating the Gut Microbiota.

Unhealthy dietary patterns are important risk factors for metabolic syndrome (MS), which is associated with gut microbiota disorder. High oleic acid peanut oil (HOPO) and extra virgin olive oil (EVOO), considered as healthy dietary oil, are rich in oleic acid and bioactive phytochemicals, yet efficacy of MS prevention and mechanisms linking to gut microbiota remain obscure. Herein, we investigated HOPO and EVOO supplementation in attenuating diet-induced MS, and the potential mechanisms focusing on modulation of gut microbiota. Physiological, histological and biochemical parameters and gut microbiota profiles were compared among four groups fed respectively with the following diets for 12 weeks: normal chow diet with ordinary drinking water, high-fat diet with fructose drinking water, HOPO diet with fructose drinking water, and EVOO diet with fructose drinking water. HOPO or EVOO supplementation exhibit significant lower body weight gain, homeostasis model assessment-insulin resistance (HOMA-IR), and reduced liver steatosis. HOPO significantly reduced cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) level, while EVOO reduced these levels without significant difference. HOPO and EVOO prevented gut disorder and significantly increased ß-diversity and abundance of Bifidobacterium. Moreover, HOPO significantly decreased abundance of Lachnospiraceae and Blautia. These findings suggest that both HOPO and EVOO can attenuate diet-induced MS, associated with modulating gut microbiota.

The differential effects of high-fat and high- -fructose diets on the liver of male albino rat and the proposed underlying mechanisms.

BACKGROUND: The Western-style diet is characterised by the high intake of energy- -dense foods. Consumption of either high-fructose diet or saturated fat resulted in the development of metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Many researchers studied the effect of high-fat diet (HFD), high-fructose diet (HFruD) and high-fructose high-fat diet (HFHF) on the liver. The missing data are the comparison effect of these groups i.e. are effects of the HFHF diet on the liver more pronounced? So, this study was designed to compare the metabolic and histopathological effect of the HFD, HFruD, and HFHF on the liver. The proposed underlying mechanisms involved in these changes were also studied. MATERIALS AND METHODS: Twenty four rats were divided into four groups: con- trol, HFD, HFruD, and HFHF. Food was offered for 6 weeks. Biochemical, light microscopic, immunohistochemical (Inducible nitric oxide synthase [iNOS] and alpha-smooth muscle actin [α-SMA]), real-time polymerase chain reaction (gene expression of TNF-α, interleukin-6, Bax, BCL-2, and caspase 3), histomorphometric analysis and oxidative/antioxidative markers (thiobarbituric acid reactive substances [TBARS], malondialdehyde [MDA]/glutathione [GSH] and superoxide dismutase [SOD]) were done. RESULTS: The HFD, HFruD and HFHF groups developed a cluster of liver disorders; steatosis, necrosis, inflammation, apoptosis, ballooning degeneration and cytopla- smic vacuolations. Internal metabolic impairments include elevated serum levels of glucose, triglycerides, low density lipoprotein and decreased serum levels of high density lipoprotein and albumin. The immunoreaction of the α-SMA and iNOS was strong in these groups. The oxidant markers (MDA and TBARS) were elevated, while the antioxidant markers (SOD and GSH) were decreased. The area per cent of collagen, inflammatory markers, caspase 3 and Bax were elevated, while the BCL-2/Bax ratio was decreased. The decrease in PAS, antioxidant markers and the elevation of the α-SMA, iNOS, inflammatory and oxidant markers were obvious in the HFHF when compared to that of the other groups. CONCLUSIONS: High-fat diet, HFruD, and HFHF developed morphologic hepatic changes ranging from steatosis to necrosis and inflammation, besides the deve- lopment of internal metabolic impairments. The chief factors of hepatic injury were fat accumulation in the hepatocytes, oxidative stress and highly elevated iNOS. Compared to the other groups, HFHF's effect was more prominent.