High-fat High-fructose Diet Research Articles

Long-term consumption of high-fat fructose diet increased the pancreatic-derived factor level and impaired glucose and lipid metabolisms in male rats

Long-term consumption of high-fat fructose diet increased the pancreatic-derived factor level and impaired glucose and lipid metabolisms in male rats

1626-P: Activation of Cardiac Mitochondrial Akt1 Enhanced Myocardial Fatty Acid Utilization, Protected against Diabetic Cardiomyopathy, and Improved Whole Body Fat Distribution

Insulin stimulates Akt1 translocation to cardiac mitochondria, and we have recently shown that inhibition of cardiac mitochondria Akt1 led to mitochondrial dysfunction and cardiomyopathy. However, whether activation of mitochondrial Akt1 in cardiac muscle can protect against the development of diabetic cardiomyopathy is not known. To this end, we have generated an inducible heart-specific transgenic mouse harboring a mitochondria-targeting constitutively active Akt1 (CAMCAKT). Long-term high fat-high fructose diet (HFFD) caused myocardial hypertrophy, fibrosis and ventricular dysfunction in control mice, but the impact of HFFD were attenuated in the CAMCAKT mice. After just two months on HFFD, expression of Col1a1 and Col3a1 in CAMCAKT mice were lower than controls (p<0.01). After five months on HFFD, ejection fraction in CA mice was 17 % higher than in controls while fractional shortening was 22% higher (p<0.05). This indicated that activation of mitochondrial Akt protected myocardium against the development of cardiomyopathy in diet-induced diabetes. Metabolically, cardiac mitochondrial Akt1 increased fatty acid uptake in the cardiac muscle, which resulted in redistribution of whole-body fatty acid metabolism. Dynamic PET scans revealed a 65% increase (p<0.001) in heart uptake of fatty acid reporter [18F]fluoro-4-thia-oleate in CAMCAKT mice. CAMCAKT mice had 15% less body fat, 30% lower total cholesterol and expended 13% more energy, compared to controls (p<0.05). Interestingly, fatty liver was reduced in the CAMCAKT mice (p<0.05), suggesting that cardiac mitochondrial Akt modulated fat deposition in the liver by higher myocardial fatty acid metabolism. In summary, activating cardiac mitochondrial Akt protected against diabetic cardiomyopathy, attenuated fatty liver, and induced whole body metabolism in this murine model of diet-induced diabetes. Disclosure A.Ta: None. Y.Chen: None. J.Li: None. E.Salem: None. P.H.Wang: Research Support; ViaCyte, Inc. Funding National Institutes of Health (R01HL096987); Ko Family Foundation

1654-P: Hepatic FGF21 Is Required for Curcumin and Resveratrol to Exert Their Metabolic Beneficial Effect in Male Mice

Intensive investigations have shown the profound metabolic beneficial effect of dietary intervention with plant polyphenols including curcumin and resveratrol. Recent studies have also shown that hepatic FGF21 is among the targets of dietary polyphenol intervention as well as intermittent fasting or nutritional restriction. Here we assessed whether hepatic FGF21 is required for dietary polyphenol intervention on metabolic homeostasis in mice on high fat high fructose diet (HFHF) challenge. Liver specific FGF21 null mice (Lfgf21-/-) were generated by mating Alb-Cre mice with Fgf21fl/fl mice. No appreciable defect on glucose disposal was observed in male or female Lfgf21-/- mice when they were fed with regular chow diet. In chow diet fed male but not female Lfgf21-/- mice, fat tolerance was impaired, associated with elevated fasting plasma TG level and reduced hepatic expression of Ehhadh and Ppargc1 (two downstream targets of FGF21). Following HFHF challenge, the control Fgf21fl/fl male mice exhibited response to 12-week curcumin intervention on reducing body weight, serum and hepatic TG elevation, and on improving fat tolerance. Those beneficial effects were absent in male Lfgf21-/- mice. In high fat diet challenged wild type mice, concomitant resveratrol intervention exhibited anticipated metabolic beneficial effect, associated with increased hepatic FGF21 mRNA and protein expression. Importantly, the metabolic beneficial effects of resveratrol intervention were observed in HFHF challenged Fgf21fl/fl mice but not in Lfgf21-/- mice. In wild type or transgenic female mice, we did not see appreciable beneficial effect with resveratrol intervention. Together we introduced a transgenic mouse model into the investigation of metabolic function of dietary intervention. We conclude that hepatic FGF21 is required for curcumin or resveratrol to exert its beneficial effect in male mice. Disclosure W.Shao: None. J.Feng: None. T.Jin: None. Funding Canadian Institutes of Health Research

THE EFFECTIVENESS OF ETHANOL EXTRACT OF JAMBLANG LEAVES (Syzygium cumini L.) IN INCREASING HDL LEVELS IN WISTAR RATS MODELS OF METABOLIC SYNDROME

One of the characteristics of metabolic syndrome (MetS) is the low high-density lipoprotein (HDL) levels. Jamblang leaves (Syzygium cumini L.) contain various phytochemicals, which have antihyperglycemic, antihyperlipidemic, and antioxidant properties. This study aims to demonstrate the effectiveness of ethanol extract of jamblang leaves in increasing HDL levels in the Wistar rats model of MetS. A pretest-posttest with a control group design was conducted using 30 male Wistar rats, divided into five groups randomly, with six rats for each group. Here, KN means normal control group, K- negative control group, and P1, P2, and P3: treatment groups that were administered the 100 mg/kg/day, 150 mg/kg/day, and 200 mg/kg/day of ethanol extract of jamblang leaves for 28 days, respectively. The rat MetS model was developed by administering the high-fat fructose diet and streptozotocin-nicotinamide. The data were analyzed using paired t-test and one-way ANOVA (α=0.05). This study found that extract administration in P2 and P3 increased HDL levels significantly, but not with the P1 group. However, HDL levels in P1 were significantly higher compared to the K- group. Moreover, increasing the dose was significantly followed by higher HDL levels, although the highest dose did not reach the HDL level as in the KN group.

Metabolic Syndrome in Hypertriglyceridemic Rats: Effects of Antioxidants.

Long-lasting disturbances in lipid and glucose metabolism present in metabolic syndrome (MetS) lead to serious cardiovascular diseases. The study was aimed to evaluate the effect of natural antioxidant vitamin E (VitE, 100 mg/kg/day, p.o.) on basal biochemical and physiological parameters characterizing MetS and on the changed function of the heart. Furthermore, the possible potentiation of VitE effect by synthetic pyridoindole antioxidant SMe1EC2 (SMe, 15 mg/kg/day, p.o.) was also tested. MetS was induced in hereditary hypertriglyceridemic rats (HTG) by the 5 weeks administration of high-fat fructose diet (HFFD: 1 % cholesterol, 7.5 % pork lard, 10 % fructose). The heart function was tested using Langendorff preparation under constant pressure. The functional parameters of isolated heart, dysrhythmias and evoked fibrillations were evaluated in conditions of ischemia-reperfusion. The HFFD increased body weight gain and serum levels of total cholesterol, low-density lipoproteins and blood glucose. The HFFD significantly increased heart flow and force of contraction, compared to standard diet (SD). During the reperfusion, the HFFD caused the increase of the ventricular premature beats number at the expense of decreasing the duration of serious dysrhythmias (ventricular tachycardias and fibrillations). The addition of VitE, SMe or their combination to the HFFD decreased body weight gain, depressed blood pressure, improved particular biochemical parameters. The combination of VitE and SMe suppressed the occurrence of serious dysrhythmias. Our data indicate that the HFFD-related disturbances led to alterations within pathophysiology in HTG rats. The results showed that a combination of antioxidants might have the potential to amend disorders accompanying MetS.

Physalis alkekengi L. Calyx Extract Alleviates Glycolipid Metabolic Disturbance and Inflammation by Modulating Gut Microbiota, Fecal Metabolites, and Glycolipid Metabolism Gene Expression in Obese Mice.

Physalis alkekengi L. calyx (PC) extract can relieve insulin resistance and has glycemic and anti-inflammatory effects; however, the potential mechanisms related to gut microbiota and metabolites remain elusive. This study aimed to understand how PC regulates gut microbiota and metabolites to exert anti-obesogenic effects and relieve insulin resistance. In this study, a high-fat high-fructose (HFHF)-diet-induced obesity C57BL/6J male mice model with glycolipid metabolism dysfunction was established, which was supplemented with the aqueous extract of PC daily for 10 weeks. The results showed that the PC supplementation could effectively cure the abnormal lipid metabolism and maintain glucose metabolism homeostasis by regulating the expression of adipose metabolic genes and glucose metabolism genes in the liver, thereby effectively alleviating the inflammatory response. PC treatment also increased the contents of fecal short-chain fatty acids (SCFAs), especially butyric acid. PC extract could restore the HFHF-disrupted diversity of gut microbiota by significantly increasing the relative abundance of Lactobacillus and decreasing those of Romboutsia, Candidatus_Saccharimonas, and Clostridium_sensu_stricto_1. The negative effects of the HFHF diet were ameliorated by PC by regulating multiple metabolic pathways, such as lipid metabolism (linoleic acid metabolism, alpha-linolenic acid metabolism, and sphingolipid metabolism) and amino acid metabolism (histidine and tryptophan metabolism). Correlation analysis showed that among the obesity parameters, gut microbiota and metabolites are directly and closely related. To sum up, this study suggested that PC treatment exhibited therapeutic effects by regulating the gut microbiota, fecal metabolites, and gene expression in the liver to improve glucose metabolism, modulate adiposity, and reduce inflammation.

Antioxidative Effects of Black Currant and Cornelian Cherry Juices in Different Tissues of an Experimental Model of Metabolic Syndrome in Rats.

A Western-style diet, rich in fat and simple sugars, is the main risk factor for a significant number of chronic diseases and disorders, as well as for a progression of metabolic syndrome (MetS). One of the key mechanisms involved in MetS development is increased oxidative stress caused by the accumulation of body fat. Some dietary polyphenols have shown a protective role in preventing oxidative-stress-induced damage. We investigated the difference in the oxidative response of plasma, liver, and visceral adipose tissue in rats fed with a high-fat high-fructose (HFF) diet for ten weeks, and the effectiveness of polyphenol-rich juices (black currant (BC) and cornelian cherry (CC)) in HFF-diet-induced oxidative stress prevention. The most prominent impact of the HFF diet on redox parameters was recorded in the liver, whereas adipose tissue showed the most potent protection mechanisms against oxidative stress. Consumption of both juices decreased advanced oxidation protein product (AOPP) level in plasma, increased paraoxonase1 (PON1) activity in the liver, and significantly decreased total oxidative status (TOS) in adipose tissue. BC exerted stronger antioxidative potential than CC and decreased the superoxide anion radical (O2•-) level in the liver. It also reduced TOS, total antioxidative status (TAS), and malondialdehyde (MDA) concentration in adipose tissue. The multiple linear regression analysis has shown that the best predictors of MetS development, estimated through the increase in visceral adiposity, were superoxide dismutase (SOD), AOPP, TOS, and TAS. The consumption of polyphenol-rich juices may provide a convenient approach for the systemic reduction of oxidative stress parameters.

Cholecalciferol Prevent Obesity in Rats Under High Fat High Fructose Diet

Obesity is an accumulation of fat body condition due to calories and energy imbalance. Obesity often coexists with low vitamin D status. Low vitamin D status is known to establish abnormality in lipid profile and increasing weight. This study aims to look at the effect of the dose and duration of Cholecalciferol supplementation on lipid profiles in male rats induced by high fat high fructose diet. In this study, we conducted an experiment using a randomized pre and posttest control group design. This study analyzed 3 groups of male Sprague Dawley strain rats that were induced with a high fat high fructose diet to become diet-induced obesity rats. Each group either receives cholecalciferol in the amount of 2.500 IU/200gr/day in P1 group, 5.000IU/200gr/day in P2 group, and 10.000 IU/200gr/day in P3 group for 8 weeks. Lipid profile outcomes analyzed include levels of total cholesterol, triglycerides, High-density lipoprotein (HDL), and low-density lipoprotein (LDL). Cholecalciferol supplementation resulted in significant differences between all lipid parameters. Total cholesterol levels are lowest in the P3 group with a mean of 102.09±2.45. followed by P2 (115.80±3.98) and P1 group (138.33±4.82), and highest in the control group (196.52±4.36). Triglyceride levels are also lowest in the P3 group with a mean of 76.03±3.81, followed by the P2 (115.80±3.98) and P1 (138.33±4.82) groups, with the highest in the control group (134.46±5.84). HDL levels are instead highest in the P3 group with a mean of 80.93±8.29, followed by P2 (77.98±10.38) and P1 (66.54±7.25) group, while lowest in the control group (25.45±2.32). LDL levels are lowest on the P3 group with a mean of 33.71±2.49, followed by P2 (38.72±1.41), and P1 (47.62±2.76) group, while highest in the control group with a mean of 82.96±1.88. Cholecalciferol supplementation was found to provide a beneficial effect across all lipid profile outcomes in this study such as total cholesterol, triglyceride, HDL, and LDL in high fat high fructose induced male Sprague Dawley rats.

Histological and immunohistochemical study of the effect of liraglutide in experimental model of non-alcoholic fatty liver disease

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is known as the accumulation of triglycerides in liver without alcohol consumption. Liraglutide is an analogue of glucagon-like peptide-1 hormone (GLP-1). It is known to decrease blood glucose, body weight and food intake. The present study is designed to study the effect of liraglutide on the experimental model of NAFLD. Thirty-six adult male albino rats were divided into three groups. Group I was the control group. Group II (FLD group) received a high-fat fructose diet for 16 weeks. Group III (FLD + Lira) received high-fat fructose diet daily for 16 weeks and were injected with Liraglutide intraperitoneally at a dose of 0.6 mg/kg/day in the last 4 weeks. Liver sections were prepared for histological, immunohistochemical and Western blot study of alpha smooth muscle actin and beclin 1. Group II showed macrovesicular and microvesicular steatosis, a strong positive immunoreaction of αSMA (alpha smooth muscle actin) and a weak positive immunoreaction of beclin 1. Group III showed a much better histological picture and a moderate positive immunoreaction of αSMA and beclin 1. In conclusion, liraglutide could treat NAFLD by improving hepatic steatosis and fibrosis, regulating lipid profile and liver functions, and enhancing autophagy.

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.

Could vitamin D protect against high fat diet induced damage in the arcuate nucleus in the rat: histological, immunohistochemical and ultrastructural study

ABSTRACT Obesity is a serious health issue. As regard, the central nervous system, obesity induces neuronal damage. Vitamin D has well-known anti-inflammatory and neuroprotective effects. To detect if vitamin D protects against damage in the arcuate nucleus induced by a high fat-high fructose diet. Forty adult rats were used, and four groups were formed. Group I (negative control) kept on a standard chow diet for six weeks, Group II (positive control) received vitamin D orally once every other day for six weeks, Group III (high fat-high fructose treated group) was given high fat-high fructose diets for six weeks and Group IV (high fat-high fructose and vitamin D treated group) were given high fat-high fructose diets concomitantly with vitamin D for six weeks. High fat-high fructose diet markedly caused histological changes in arcuate neurons as nuclei appeared darkly stained and shrunken with condensed chromatin, and the nucleolus became less prominent. The cytoplasm appeared rarefied with loss of most of the organelles. An increase in neuroglial cells was noticed. The synaptic area showed sparse degenerated mitochondria and a disrupted presynaptic membrane. A high-fat diet has a damaging effect on arcuate neurons and vitamin D alleviates these effects.

Three Varieties of Grape Pomace, with Distinctive Extractable:Non-Extractable Polyphenol Ratios, Differentially Reduce Obesity and Its Complications in Rats Fed a High-Fat High-Fructose Diet.

Grape pomace is a commonly discarded by-product characterized by high extractable (EPP) and non-extractable (NEPP) polyphenol contents which exhibits anti-obesogenic effects. However, the relevance of each fraction needs to be elucidated. In this work, we examined the effects of three pomaces with different concentrations of EPPs and NEPPs on metabolic alterations associated with obesity. The NEPP:EPP ratio of the grape pomaces was 1.48 for Malbec, 1.10 for Garnacha, and 5.76 for Syrah grape varieties. Rats fed a high-fat high-fructose diet supplemented with Malbec grape pomace (HFFD + MAL) Syrah grape pomace (HFFD + SYR) or Garnacha grape pomace (HFFD + GAR) showed significantly less weight gain: 20%, 15%, and 12% less, respectively, compared to HFFD controls. The adiposity index was also significantly decreased by 20% in the HFFD + MAL and HFFD + SYR groups, and by 13% in the HFFD + GAR group. Serum triglycerides were significantly decreased by 46% in the HFFD + MAL group and by 31% in the HFFD + GAR group, compared to the HFFD group, but not in the HFFD + SYR group. All pomace supplementations regulated postprandial glucose in an oral glucose tolerance test. Therefore, grape pomaces containing both EPPs and NEPPs exert beneficial effects on body weight and glucose homeostasis, while EPPs seem to control triglyceride levels more effectively.

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, β-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.

Faecalibacterium prausnitzii prevents hepatic damage in a mouse model of NASH induced by a high-fructose high-fat diet.

Nonalcoholic steatohepatitis (NASH) is an advanced nonalcoholic fatty liver disease characterized by chronic inflammation and fibrosis. A dysbiosis of the gut microbiota has been associated with the pathophysiology of NASH, and probiotics have proven helpful in its treatment and prevention. Although both traditional and next-generation probiotics have the potential to alleviate various diseases, studies that observe the therapeutic effect of next-generation probiotics on NASH are lacking. Therefore, we investigated whether a next-generation probiotic candidate, Faecalibacterium prausnitzii, contributed to the mitigation of NASH. In this study, we conducted 16S rRNA sequencing analyses in patients with NASH and healthy controls. To test F. prausnitzii could alleviate NASH symptoms, we isolated four F. prausnitzii strains (EB-FPDK3, EB-FPDK9, EB-FPDK11, and EB-FPYYK1) from fecal samples collected from four healthy individuals. Mice were maintained on a high-fructose high-fat diet for 16 weeks to induce a NASH model and received oral administration of the bacterial strains. Changes in characteristic NASH phenotypes were assessed via oral glucose tolerance tests, biochemical assays, and histological analyses. 16S rRNA sequencing analyses confirmed that the relative abundance of F. prausnitzii reduced significantly in patients with NASH compared to healthy controls (p < 0.05). In the NASH mice, F. prausnitzii supplementation improved glucose homeostasis, prevented hepatic lipid accumulation, curbed liver damage and fibrosis, restored damaged gut barrier functions, and alleviated hepatic steatosis and liver inflammation. Furthermore, real-time PCR assays documented that the four F. prausnitzii strains regulated the expression of genes related to hepatic steatosis in these mice. Our study, therefore, confirms that the administration of F. prausnitzii bacteria can alleviate NASH symptoms. We propose that F. prausnitzii has the potential to contribute to the next-generation probiotic treatment of NASH.

AMPK activation by AICAR reduces diet induced fatty liver in C57BL/6 mice

Dysregulation of 5′-adenosine monophosphate-activated protein kinase (AMPK) occurs in metabolic disorders including non-alcoholic fatty liver disease (NAFLD) which makes it a molecular target for treatment. An AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) alleviates NAFLD in experimental rats, however the specific mechanism remains to be explored. We aimed to study the effect of AICAR on lipid levels, oxidant-antioxidant balance, AMPK and mTOR activation and FOXO3 gene expression in liver of mice model. Fatty liver was induced in two groups of C57BL/6 mice (groups 2 and 3) by providing a high fat high fructose diet (HFFD) for 10 weeks while groups 1 and 4 animals were fed normal pellet. For the last two weeks, groups 3 and 4 were administered AICAR (150 mg/kg bw/day, i.p.) while groups 1 and 2 were administered saline. AICAR decreased fatty liver, decreased glucose and insulin in circulation, prevented the accumulation of triglycerides and collagen and ameliorated oxidative stress in HFFD fed mice. At the molecular level, AICAR upregulated FOXO3 and p-AMPK expression and reduced p-mTOR expression. AMPK activation may involve FOXO3 in protection against NAFLD. The role of AMPK, mTOR and FOXO3 crosstalk in NAFLD needs to be characterised in future.

The Mechanisms of Neochlorogenic Acid (3-Caffeoylquinic Acid) in Improving glucose and Lipid Metabolism in Rats with Insulin Resistance Induced by A High Fat-High Fructose Diet

This study investigated the effects and the mechanism of actions of neochlorogenic acid (3-caffeoylquinic acid; 3-CQA) on glucose and lipid metabolism in rats fed a high fat-high fructose diet (HFFD). Male rats were fed HFFD (40 % lard and 20 % fructose) for 16 weeks. At the 10th week, the HFFD rats were split into 3 groups: HFFD receiving distilled water (HFFD control group), HFFD receiving 3-CQA 50 mg/kg and HFFD receiving metformin 200 mg/kg once daily for a further 6 weeks. At the end of treatment, fasting blood glucose (FBG), oral glucose-tolerance test (OGTT), lipid profile, insulin, leptin, adiponectin, markers of oxidative stress, and hepatic triglyceride content were measured. Liver, adipose tissue, and skeletal muscle were collected for histological, gene and protein examinations. Compared to the HFFD control group, the 3-CQA group exhibited significantly reduced FBG, insulin and leptin levels, and improved OGTT. Serum adiponectin increased and lipid profiles were normalized. Hepatic triglyceride was reduced with a decrease in lipid droplets in liver histological sections. Levels of serum SOD and CAT activity, and MDA were reversed by 3-CQA treatment. Moreover, 3-CQA significantly reduced the expression of adipocyte pro-inflammatory cytokine genes (MCP-1, TNF-α, and IL-6), hepatic lipogenic genes (SREBP1c, FAS, and GPAT), and hepatic gluconeogenic genes (PEPCK and G6Pase). Additionally, 3-CQA increased expression of muscle GLUT4 gene, and of GLUT4 protein with increased p-AKT and p-AMPK in skeletal muscle. In conclusion, 3-CQA improves glucose and lipid metabolism plausibly by decreasing oxidative stress and inflammation-induced insulin resistance, downregulating the expression of lipogenic and gluconeogenic genes, and enhancing insulin signaling in HFFD-induced insulin-resistant rats. HIGHLIGHTS Neochlorogenic acid (3-CQA) improves glucose and lipid metabolism by decreasing insulin resistance Neochlorogenic acid (3-CQA) deceases insulin resistance due to its activities in ameliorating obesity, oxidative stress, and adipose tissue inflammation The beneficial effects of Neochlorogenic acid (3-CQA) to improve glucose and lipid homeostasis may be mediated via suppression of hepatic glucose production and lipogenesis, and activation of muscle glucose uptake and AKT and AMPK pathways GRAPHICAL ABSTRACT

6-gingerol ameliorates weight gain and insulin resistance in metabolic syndrome rats by regulating adipocytokines

Metabolic syndrome (MetS) can lead to increase of insulin resistance (IR) and visceral adipose tissue production of adipocytokines. 6-gingerol is known to have antioxidant and anti-inflammatory activities. Aim of this study is to investigate the effects of 6-gingerol on high-fat high-fructose (HFHF) diet-induced weight gain and IR in rats through modulation of adipocytokines. To induce MetS, male Sprague-Dawley rats were fed with a HFHF diet for 16 weeks and at Week 8, single-dose low-dose streptozotocin (22 mg/kg) were intraperitoneally injected. After 8 weeks of HFHF diet feeding, the rats were treated orally with 6-gingerol (50, 100, and 200 mg/kg/day) once daily for 8 weeks. At the end of the study, all animals were terminated, serum, liver, and visceral adipose tissues were harvested for biochemical analysis including the measurements of total cholesterol, triglycerides, HDL-cholesterol, fasting plasma glucose, insulin, leptin, adiponectin, proinflammatory cytokines (TNF-α and IL-6) and liver and adipose tissue histopathology. Biochemical parameters namely serum total cholesterol (243.7 ± 127.6 vs 72.6 ± 3 mg/dL), triglycerides (469.2 ± 164.9 vs 49.3 ± 6.3 mg/dL), fasting plasma glucose (334 ± 49.5 vs 121 ± 8.5 mg/dL), HOMA-IR (0.70 ± 0.24 vs 0.32 ± 0.06), and leptin (6.19 ± 1.24 vs 3.45 ± 0.33 ng/mL) were significantly enhanced, whereas HDL-cholesterol (26.2 ± 5.2 vs 27.9 ± 1.1 mg/dL) and adiponectin level (14.4 ± 5.5 vs 52.8 ± 10.7 ng/mL) were lowered in MetS vs normal control. Moreover, MetS were marked a significant increase in body weight and proinflammatory cytokines. Treatment with 6-gingerol dose-dependently restored all of those alterations towards normal values as well as the accumulation of lipid in liver and adipose tissues. These findings demonstrate that 6-gingerol, in a dose-dependent mode, showed capability of improving weight gain and IR in MetS rats through modulation of adipocytokines.

Soybean Elicited with Saccharomyces cerevisiae and Light Attenuates Stromal-Derived Factor-1 Associated with CXCR4 in High-Fat/Fructose Diet Mice

Abstract Soybean elicited with microorganisms transforms its phytochemical content which is rich in anti-inflammatory action. However, the potential effect of the elicited soybean extract (ESE) on the maintenance of the stromal-derived factor-1 (SDF-1) regulatory system in the spleen, thymus, hepar, and bone marrow in high-fat/fructose diet (HFFD) mice is yet to be investigated. In our study, the spleen, thymus, hepar, and femurs were collected and isolated at the end of the experiment. The expression of SDF-1 in hepar, CD4+, CD8+, T cells, and B220+ cells was measured using flow cytometry analysis. To determine the interaction between the active compound of ESE and CXCR4, docking analysis was conducted using PyRx 0.8. The expression of splenic and thymic CD4+SDF-1+, CD8+SDF-1+, and hepatic SDF-1+ was elevated in HFFD mice but not in normal diet (ND) mice. ESE had significantly declined (P &lt; 0.05) in CD4+SDF-1+ and CD8+SDF-1+ T-cells subsets. ESE treatment improved the development of B cells in HFFD mice. The molecular docking analysis identified glyceollin I with the strongest affinity of −8.4 kcal/mol. The results suggest that glyceollin I has a positive effect as a CXCR4 inhibitor. ESE supplementation was significant in maintaining the regulatory system of SDF-1 expressed by CD4+, CD8+, hepatocyte, and B220+ cells in HFFD associated with obesity Keywords: CXCR4, Glyceollin, High-fat, High-fructose, SDF-1, Soybean

Alpha-ketoglutarate partially alleviates effects of high-fat high-fructose diet in mouse muscle.

Consumption of high-calorie diets leads to excessive accumulation of storage lipids in adipose tissue. Metabolic changes occur not only in adipose tissue but in other tissues, too, such as liver, heart, muscle, and brain. This study aimed to explore the effects of high-fat high-fructose diet (HFFD) alone and in the combination with alpha-ketoglutarate (AKG), a well-known cellular metabolite, on energy metabolism in the skeletal muscle of C57BL/6J mice. Five-month-old male mice were divided into four groups - the control one fed a standard diet (10 % kcal fat), HFFD group fed a high-fat high-fructose diet (45 % kcal fat, 15 % kcal fructose), AKG group fed a standard diet with 1 % sodium AKG in drinking water, and HFFD + AKG group fed HFFD and water with 1 % sodium AKG. The dietary regimens lasted 8 weeks. Mice fed HFFD had higher levels of storage triacylglycerides, lower levels of glycogen, and total water-soluble protein, and higher activities of key glycolytic enzymes, namely hexokinase, phosphofructokinase, and pyruvate kinase, as compared with the control group. The results suggest that muscles of HFFD mice may suffer from lipotoxicity. In HFFD + AKG mice, levels of the metabolites and activities of glycolytic enzymes did not differ from the respective values in the control group, except for the activity of pyruvate kinase, which was significantly lower in HFFD + AKG group compared with the control. Thus, metabolic changes in mouse skeletal muscles, caused by HFFD, were alleviated by AKG, indicating a protective role of AKG regarding lipotoxicity.

Use of high-fat high-fructose diet for a model of metabolic syndrome in Wistar rats: challenges remain

Metabolic syndrome (MetS) is a global public health challenge and one of the main risk factors for cardiovascular diseases. Its pandemic prevalence created a demand for developing a relevant model system for deep insight into the molecular basis of MetS. Animal models, especially Wistar rats, are commonly used for that purpose. However, there are no standardized protocols in terms of the diet, strain, or age of rats used for the development of MetS. Studies have mostly used a high-fat high-fructose (HFHF) diet in Wistar rats but have reported inconsistent results; thus the main aim of this study was to examine the effects of the HFHF diet on inducing MetS in Wistar rats. We used two different sub-strains of Wistar rats – Hannover and Kyoto – of two different age groups (8 weeks and 4 months). Animals were placed on a modified diet, standard chow diet enriched with 25% fat and 20% fructose. Following 8 weeks of treatment, all groups were tested for indicators of MetS and the treatment was extended to 16 weeks for groups that developed some of the required parameters. None of the tested groups developed MetS after 16 weeks of HFHF diet, suggesting that the HFHF diet is not sufficient to develop at least three out of five (visceral obesity, high fasting glucose, high triglyceride, low HDL-cholesterol, high blood pressure) needed parameters. Based on our results, the addition of some pharmacological agents (e.g., cholic acid) is necessary for establishing a rat model system of MetS.