High-fat High-fructose Diet Research Articles

Comparative profiling of gut microbiota and metabolome in diet-induced obese and insulin-resistant C57BL/6J mice

Diet-based models are commonly used to investigate obesity and related disorders. We conducted a comparative profiling of three obesogenic diets HFD, high fat diet; HFHF, high fat high fructose diet; and HFCD, high fat choline deficient diet to assess their impact on the gut microbiome and metabolome. After 20 weeks, we analyzed the gut microbiota and metabolomes of liver, plasma, cecal, and fecal samples. Fecal and plasma bile acids (BAs) and fecal short-chain fatty acids (SCFAs) were also examined. Significant changes were observed in fecal and cecal metabolites, with increased Firmicutes and decreased Bacteroidetes in the HFD, HFHF, and HFCD-fed mice compared to chow and LFD (low fat diet)-fed mice. Most BAs were reduced in plasma and fecal samples of obese groups, except taurocholic acid, which increased in HFCD mice's plasma. SCFAs like acetate and butyrate significantly decreased in obesogenic diet groups, while propionic acid specifically decreased in the HFCD group. Pathway analysis revealed significant alterations in amino acid, carbohydrate metabolism, and nucleic acid biosynthesis pathways in obese mice. Surprisingly, even LFD-fed mice showed distinct changes in microbiome and metabolite profiles compared to the chow group. This study provides insights into gut microbiome dysbiosis and metabolite alterations induced by obesogenic and LFD diets in various tissues. These findings aid in selecting suitable diet models to study the role of the gut microbiome and metabolites in obesity and associated disorders, with potential implications for understanding similar pathologies in humans.

High-fat high-fructose diet and alpha-ketoglutarate affect mouse behavior that is accompanied by changes in oxidative stress response and energy metabolism in the cerebral cortex

BackgroundHigh caloric diets with high amounts of fats and sweeteners such as fructose may predispose organisms to neurodegenerative diseases. MethodsThis study aimed to examine the effects of a high-fat high-fructose diet (HFFD) on the behavior of mice, energy metabolism, and markers of oxidative stress in murine cerebral cortex. Dietary α-ketoglutarate (AKG) was chosen as a treatment which could modulate the putative effects of HFFD. ResultsWe found that HFFD stimulated locomotion and defecation in mice, whereas an AKG-supplemented diet had a proclivity to promote anxiety-like behavior. HFFD stimulated lipid peroxidation, and in turn, the AKG-supplemented diet led to a higher ratio of reduced to oxidized glutathione, higher activity of NAD(P)H:quinone oxidoreductase 1, and higher mRNA levels of UDP-glucose 6-dehydrogenase and transcription factor EB. Both diets separately, but not in combination, led to a decrease in the activities of glutathione peroxidase, glutathione S-transferase, and phosphofructokinase. All experimental diets resulted in lower levels of transcripts of genes encoding pyruvate dehydrogenase kinase 4 (PDK4), glycine N-methyl transferase, and peroxisome proliferator receptor γ co-activator 1. ConclusionsOur results show that diet supplemented with AKG resulted in effects similar to those of HFFD on the cerebral cortex, but elicited substantial differences between these two diets with respect to behavior, glutathione-dependent detoxification, and processes related to autophagy. General significanceOur study provides insight into the metabolic effects of HFFD alone and in combination with alpha-ketoglutarate in the mouse brain.

Japanese Quince Fruit Juice Exerts a Cardioprotective Effect in a Model of Diet-Induced Metabolic Syndrome in Rats

Summary The current study aimed to evaluate the influence of Japanese quince (Chaenomeles japonica) fruit juice (JQFJ) on the myocardium and on the coronary arteries of rats with diet-induced metabolic syndrome (MS). Male Wistar rats (n=50) were divided into 5 groups: Control, MS, MS+JQFJ2.5, MS+JQFJ5 and MS+JQFJ10. MS was induced with a high-fat high-fructose diet for 10 weeks. During that period, all animals were daily orally treated with distilled water (Control and MS groups) or with JQFJ at doses of 2.5 ml/kg, 5 ml/kg and 10 ml/kg (the other three groups, respectively). At the end of the experiment, the myocardium and coronary arteries were examined histopathologically. In group MS, necrotic endothelial cells and exposed basal membrane were observed. JQFJ at 2.5 ml/kg reduced the impairment but activated endothelial cells were still found. JQFJ at 5 ml/kg and 10 ml/kg prevented coronary artery endothelium damage, preserving the normal morphology. The myocardium in MS group presented with cardiomyocyte degeneration and increased distance between the cells. In group MS+JQFJ2.5, the degeneration was decreased. In groups MS+JQFJ5 and MS+JQFJ10, the histology of the myocardium resembled that of the control group. In the current histopathological evaluation, JQFJ prevented the MS-induced impairment of myocardium and coronary arteries.

Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease.

Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status. Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC). We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model. Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.

Changes in brown adipose tissue induced by resveratrol and its analogue pterostilbene in rats fed with a high-fat high-fructose diet

Natural bioactive compounds have attracted a great deal of attention since some of them can act as thermogenesis activators. In recent years, special interest has been placed on resveratrol and its analogue pterostilbene, a dimethylether derivative that shows higher bioavailability. The aim of the present study is to compare the effects of resveratrol and its derivative pterostilbene on the thermogenic capacity of interscapular brown adipose tissue (iBAT) in rats under a high-fat high-fructose diet. Rats were divided into four experimental groups: control, high-fat high-fructose diet (HFHF) and HFHF diet supplemented with 30 mg/kg body weight/day of pterostilbene (PT30) or resveratrol (RSV30), for eight weeks. Weights of adipose tissues, iBAT triglycerides, carnitine palmitoyltransferase 1A (CPT1A) and citrate synthase (CS) activities, protein levels of uncoupling protein 1 (UCP1), sirtuins (SIRT1 and 3), AMP-activated protein kinase (AMPK), glucose transporter (GLUT4), fatty acid synthase (FAS), nuclear respiratory factor (NRF1), hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), CD36 and FATP1 fatty acid transporters, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) activation and the batokines EPDR1 and NRG4 were assessed in iBAT. The results show that some key proteins related to thermogenesis were modified by either pterostilbene or resveratrol, although the lack of effects on other crucial proteins of the thermogenic machinery suggest that these compounds were not able to stimulate this process in iBAT. Overall, these data suggest that the effects of stilbenes on brown adipose tissue thermogenic capacity depend on the metabolic status, and more precisely on the presence or absence of obesity, although further studies are needed to confirm this hypothesis.

High maternal adiposity during pregnancy programs an imbalance in the lipidome and predisposes to diet-induced hepatosteatosis in the offspring.

Exposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. Females heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Female wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high-fat/fructose diet (HFFD) compared with Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams and CD or HFFD-fed Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic polyunsaturated FA (PUFA) levels compared with control offspring. Changes to saturated FA (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and Δ9 desaturase activity. High maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.

Oral administration of viable or heat-inactivated Lacticaseibacillus rhamnosus GG influences on metabolic outcomes and gut microbiota in rodents fed a high-fat high-fructose diet

High-fat High-fructose diets have been associated with metabolic disorders and gut microbiota dysbiosis. Thus, the administration of probiotic or postbiotic from the strain Lacticaseibacillus rhamnosus GG has been investigated as a protective strategy. The aim of this study was to analyze the impact of L. rhamnosus GG administration in rodents fed a high-fat high-fructose diet. Male Wistar rats with oral supplementation of L. rhamnosus GG, viable or heat-inactivated, for 6 weeks were evaluated for somatic measurements, food and energy intake, biochemical markers, and gut microbiota. The daily administration of L. rhamnosus GG, as probiotic or postbiotic, was beneficial in attenuating weight gain, visceral fat deposition and visceral hypertriglyceridemic phenotype. Furthermore, the administration of heat-inactivated L. rhamnosus GG elicited an increase of species such as Akkermansia muciniphila, Blautia glucerasea, Sarcina maxima and L. rhamnosus, where the interaction between L. rhamnosus and Blautia glucerasea attenuated metabolic markers altered by the obesogenic diet.

Chinese Sumac Fruits (Rhus chinesis Mill.) Alleviate Type 2 Diabetes in C57BL/6 Mice through Repairing Islet Cell Functions, Regulating IRS-1/PI3K/AKT Pathways and Promoting the Entry of Nrf2 into the Nucleus.

This research aimed to probe the potential alleviative effects of ethanol extracts of Chinese sumac (Rhus chinesis Mill.) fruits against type 2 diabetes mellitus (T2DM) in C57BL/6 mice induced by high-fat/high-fructose diet (HFFD) and streptozotocin. The results showed that the ethanol extracts could significantly regulate blood glucose levels, glycosylated hemoglobin, blood lipids, insulin, and insulin resistance, while also restoring endogenous oxidative stress. Pathological and immunohistochemical analyses revealed that the extracts partially restored the physiological function of islet cells. Furthermore, Western blotting results suggested that the extracts could regulate the protein expression in IRS-1/PI3K/AKT signaling pathway, and immunofluorescence findings demonstrated their potential to promote the translocation of Nrf2 into the nucleus. This study elucidated a novel finding that ethanol extracts derived from Chinese sumac fruits have the potential to alleviate symptoms of T2DM in mice. Moreover, these findings could offer valuable scientific insights into the potential utilization of R. chinensis fruits as nutritional supplement and/or functional food to prevent or ameliorate diabetes.

Adipose Tissue Protects against Hepatic Steatosis in Male Rats Fed a High-Fat Diet plus Liquid Fructose: Sex-Related Differences.

Non-alcoholic fatty liver disease is a sexual dimorphic disease, with adipose tissue playing an essential role. Our previous work showed that female rats fed a high-fat high-fructose diet devoid of cholesterol (HFHFr) developed simple hepatic steatosis dissociated from obesity. This study assessed the impact of the HFHFr diet on the male rat metabolism compared with data obtained for female rats. A total of 16 Sprague Dawley (SD) male rats were fed either a control (standard rodent chow and water) or HFHFr (high-fat diet devoid of cholesterol, plus 10% fructose in drinking water) diet for 3 months. Unlike female rats, and despite similar increases in energy consumption, HFHFr males showed increased adiposity and hyperleptinemia. The expression of hormone-sensitive lipase in the subcutaneous white adipose tissue was enhanced, leading to high free fatty acid and glycerol serum levels. HFHFr males presented hypertriglyceridemia, but not hepatic steatosis, partially due to enhanced liver PPARα-related fatty acid β-oxidation and the VLDL-promoting effect of leptin. In conclusion, the SD rats showed a sex-related dimorphic response to the HFHFr diet. Contrary to previous results for HFHFr female rats, the male rats were able to expand the adipose tissue, increase fatty acid catabolism, or export it as VLDL, avoiding liver lipid deposition.

Abstract P340: Codonopsis Lanceolata Extract Prevents Metabolic And Cardiovascular Alterations In Short-term High-fat/high-fructose Diet-fed Adolescent Rats

Fast food consumption, which has increased among adolescents, has been associated with the risk of cardio-metabolic disorders. However, the effects of short-term high-fat/high-fructose diet (HFFD) on cardiovascular and metabolic parameters in adolescent rats has not yet been evaluated. Also, preventive effects of codonopsis lanceolata (CL) in these rats are unknown. Therefore, we investigated the effects of short-term HFFD consumption on cardiovascular and metabolic factors in adolescent rats, as well as the preventive effects of CL extract. Adolescent rats were fed a 60% high-fat diet plus 10% fructose water for 2 weeks. During this time, CL extract (200 or 400 mg/kg) was administered once daily. Short-term HFFD increased visceral white adipose tissue (WAT) weight, fasting blood sugar (FBS) concentration and water intake in adolescent rats. This diet also significantly increased systolic blood pressure (SBP), heart rate, and phenylephrine-induced vasocontraction. CL extract, however, effectively reduced visceral WAT weight, FBS, SBP and heart rate in short-term HFFD-fed adolescent rats. These findings indicate that exposure to HFFD for only 2 weeks induced cardiovascular and metabolic alterations in adolescent rats and that CL extract is effective in preventing these harmful effects of short-term HFFD in adolescent rats. This work was by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021R1A2C2004118). * Corresponding author. Keywords: high-fat/high-fructose diet; adolescent; codonopsis lanceolata ; prevention; visceral white adipose tissue; fasting blood sugar; systolic blood pressure

Differential effects of PGAM5 knockout on high fat high fructose diet and methionine choline-deficient diet induced non-alcoholic steatohepatitis (NASH) in mice

BackgroundPhosphoglycerate mutase 5 (PGAM5), a phosphatase involved in mitochondrial homeostasis, is reported to be closely related to the metabolic stress induced by high-fat diet (HFD) or cold. In this study, we aimed to investigate the effects of PGAM5 on hepatic steatosis, inflammation and fibrosis in nonalcoholic steatohepatitis (NASH).Methods and resultsWe generated PGAM5 global knockout (GKO) mice and their wildtype (WT) littermates using CRISPR/CAS9. The mice were fed with a high fat high fructose (HFHF) diet for 12 weeks or a methionine choline-deficient (MCD) diet (methionine choline supplemented (MCS) as control) for 6 weeks. Hepatic PGAM5 expression was up-regulated in humans with NASH and WT mice fed with HFHF and MCS, and reduced in WT mice fed with MCD diet. In HFHF-fed mice, GKO had reduced body weight, hepatic triglyceride (TG) content and serum transaminase along with decreased hepatic pro-inflammatory and pro-fibrotic responses compared with their WT control. GKO had increased expression of antioxidative gene glutathione peroxidase-6 (GPX6) and activation of mammalian target of rapamycin (mTOR). In mice fed with MCS diet, GKO significantly increased serum TNF-α and IL-6 and decreased hepatic GPX6 mRNA expression. There was no difference in hepatic steatosis, inflammation or fibrosis between GKO and WT mice fed with MCD diet. We investigated the role of PGAM5 deficiency in a variety of cell types. In differentiated THP-1 cells, PGAM5 silencing significantly increased pro-inflammatory cytokine secretion and decreased antioxidative proteins, including nuclear factor erythroid 2- related factors (NRF2), heme oxygenase-1 (HO-1) and GPX6 without affecting mTOR activity. In HepG2 cells with steatosis, PGAM5 knockdown reduced insulin sensitivity, increased mTOR phosphorylation and reduced the expression of NRF2, catalase (CAT), HO-1 and GPX6. Conversely, PGAM5 knockdown reduced TG accumulation, increased insulin sensitivity, and increased antioxidative genes in 3T3-L1 cells, despite the up-regulation in mTOR phosphorylation.ConclusionsPGAM5-KO relieved hepatic steatosis and inflammation in HFHF model, promoted inflammation in MCS-fed mice and had no effects on the MCD-fed model. The distinct effects may be owing to the different effects of PGAM5-KO on anti-oxidative pathways in energy-dependent, possible involves mTOR, and/or cell type-dependent manner. Our findings suggest that PGAM5 can be a potential therapeutic target for NASH.

Raspberry ketone ameliorates nonalcoholic fatty liver disease in rats by activating the AMPK pathway

The current study aimed to investigate the effect of orally administered raspberry ketone (RK) on ameliorating nonalcoholic fatty liver disease (NAFLD) induced in rats by high-fat high-fructose diet (HFFD) in comparison to calorie restriction (CR) regimen. Thirty male Wistar rats were divided into two experimental groups; one was fed normal chow diet (NCD, n = 6) for 15 weeks to serve as normal control group and the other group was fed HFFD (n = 24) for 7 weeks to induce NAFLD. After induction, rats in the HFFD group were randomly allocated into four groups (n = 6 rats each). One group continued on HFFD feeding for 8 weeks (NAFLD control group). The remaining 3 groups received NCD, calorie-restricted diet, or NCD along with RK (55 mg/kg/day, orally) for 8 weeks.Like CR, RK effectively attenuated NAFLD and ameliorated the changes attained by HFFD. RK upregulated the expression of the phosphorylated AMP-activated protein kinase (P-AMPK) and fatty acid oxidation factors; peroxisome proliferator-activated receptor alpha (PPAR-α) and carnitine palmitoyltransferase-1 (CPT-1) and downregulated lipogenic factors; sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) in the hepatic tissue. Also, RK improved lipid profile parameters, liver enzymes and both body and liver tissue weights. Altogether, these findings suggest that oral administration of RK, along with normal diet, ameliorated NAFLD in a way similar to CR. This approach could be an alternative to CR in the management of NAFLD, overcoming the poor compliance to long term CR regimen.

Folate Deficiency Enhanced Inflammation and Exacerbated Renal Fibrosis in High-Fat High-Fructose Diet-Fed Mice.

The prevalence of obesity and chronic kidney disease (CKD) is increasing simultaneously and rapidly worldwide. Our previous study showed that folate deficiency increased lipid accumulation and leptin production of adipocytes. Whether folate plays a role in CKD, particularly obesity-related nephropathy remains unclear. To investigate the effects of folate deficiency on CKD in diet-induced obese mice, four groups of male C57BL/6 mice were fed either a normal-fat diet (NF) with folate (NF+f); NF without folate (NF-f); high-fat high-fructose diet (HFF) with folate (HFF+f); or HFF without folate (HFF-f) for 12 months during the study. The results showed that HFF increased not only body weight, fasting blood glucose, total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, and blood pressure, but also cytokines levels, such as interleukin (IL)-2, interferon (IFN)-γ, IL-17A/F, IL-6, monocyte chemoattractant protein (MCP)-1, and transforming growth factor (TGF)-β1. The indicators of kidney failure including urinary protein, neutrophil gelatinase-associated lipocalin (NGAL), renal type I and IV collagen deposits and leptin content, and serum creatinine were also increased by HFF. Folate-deficient diets further elevated serum TC, LDL-cholesterol, IL-6, tumor necrosis factor (TNF)-α, MCP-1, TGF-β1, and leptin, but decreased IL-10 level, and thus exacerbated renal fibrosis. To investigate the possible mechanisms of folate deficiency on renal injury, phosphorylation of pro-fibrosis signaling molecules, including signal transducer and activator of transcription (STAT)3 and small mothers against decapentaplegic (Smad)2/3, were assayed. Both HFF and folate deficiency significantly increased the phosphorylation of STAT3 and Smad2/3, suggesting synergistic effects of HFF-f on chronic renal inflammation and fibrosis. In conclusion, the results demonstrated that folate deficiency might aggravate inflammatory status and enhance renal fibrosis.

Management of metabolic syndrome by nutraceuticals prepared from chitosan and ferulic acid with or without beta-sitosterol and their nanoforms

Dyslipidemia, steatohepatitis and insulin resistance are among the components of metabolic syndrome (MS). Nutraceuticals containing chitosan, beta-sitosterol and/or ferulic acid and their nanostructures could have a potential role for management of MS. The aim of the present study was to assess the efficacy of the aforementioned nutraceuticals in treatment of MS in rat and their interaction with atorvastatin, a hypolipidemic drug. The two nutraceuticals and their nanostructures were prepared and the nanostructures were assessed by transmission electron microscope and Fourier-Transform Infra-red Spectrometry. MS was induced in rats by feeding high fructose-high fat diet (HFFD). Different groups of rats fed HFFD and treated with the different nutraceuticals, atorvastatin and atorvastatin in combination with different nutraceuticals, control fed on balanced diet and control consumed HFFD without treatments were run. Plasma glucose, lipid profile, aminotransferases activity, total antioxidant capacity, malondialdehyde, urea, creatinine, insulin, high sensitivity C-reactive protein, and adiponectin were assessed along with calculation of insulin resistance. Liver fat and histopathology were investigated. All nutraceuticals in original and nanostructures showed beneficial effects in the treatment of MS, superiority was ascribed to nutraceuticals composed of chitosan and ferulic acid in both forms. A more promising treatment of MS belonged to atorvastatin administered with the different nutraceuticals.

Dry heat whole Sorghum BRS 305 flour modulate satiety and improves antioxidant response in brain of Wistar rats fed with high-fat high-fructose diet

Sorghum BRS 305 (Sorghum bicolor L. Moench) is a cereal with high tannins and anthocyanins content and keep better the resistant starch when submitted to dry heat treatment. Our objective was to investigate the effects of BRS 305 dry heat treatment whole sorghum flour on satiety and antioxidant response in brain and adipose tissue of Wistar rats fed with a high fat high fructose diet (HFHF). Male Wistar rats were divided in two groups: control (n = 8) and HFHF (n = 16) for eight weeks. After, animals of HFHF group were divided: HFHF (n = 8) and HFHF + BRS 305 sorghum whole flour (n = 8), for 10 weeks. Sorghum consumption reduced gene expression of leptin, resistin, and endocannabinoid receptor 1 type (CB1) in adipose and brain tissues compared to HFHF group. In brain, sorghum consumption also promotes reduction in neuropeptide Y (NPY) gene expression. BRS305 sorghum consumption improved gene expression of sirtuin-1 (SIRT1) in adipose tissue, and in the brain increased heat shock protein 72 (HSP72), erythroid-derived nuclear factor 2 (NRF2), peroxisome proliferator-activated receptor alpha (PPARα), superoxide dismutase (SOD) and catalase activity compared to HFHF. In silicoanalysis showed interaction with PPARα, CB1, and leptin receptors. Advanced glycation end products (AGEs) concentrations in group HFHF + sorghum did not differ from HFHF group. Advanced glycation end products receptors (RAGEs) concentrations did not differ among experimental groups. Then, BRS 305 sorghum submitted to dry treatment was able to modulate gene expression of markers related to satiety and improve antioxidant capacity of rats fed with HFHF diet.

Effect of Fenugreek Seeds and Its Bioactive Compounds on High Fructose High Fat Diet Induced Abnormalities in Sprague Dawley Rats

Fenugreek seeds are rich in various essential compounds and these components play a significant role in healing and treating diseases by regulating several biological activities. The purpose of this study was to evaluate the metabolic effects of fenugreek seed (FS) and its bioactive compounds such as Fenu pulse (FP), Fenu fiber (FF), Diosgenin (Dsg) in High Fructose High Fat (HFHF) induced diabetic rats.After hyperglycemia was confirmed in HFHF rats compared with controls, further HFHF groups were supplemented with FS, FP, FF, Dsg, and combinations of these compounds. The HFHF diet was given for 4 months which increased the body weight, body fat percentage, and decreased lean body mass (LBM) and fat-free mass (FFM) percentage compared with controls rats. The diet combination was continued for another four months and it did not show any further effect on their body composition. There was a significant but marginal effect on fasting glucose and insulin, so the animals did not have overt hyperglycemia, let alone be diabetic. The FS or its components individually or in combination within a diet-induced rat model of diabetes showed no significant antidiabetic effect (glucose tolerance/metabolic parameters), both in the fasting and fed states wherein it elevated the levels of total and HDL cholesterol but not triglycerides (TG) upon continuous feeding for four months. The reduced effect of FS and its components appears due to moderate hyperglycemia in the HFHF rats.

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.