High-fat High-fructose Diet Research Articles

Acute and chronic metabolic effects of carvedilol in high-fructose, high-fat diet-fed mice: implication of β-arrestin2 pathway.

We aimed to investigate the acute and chronic effects of carvedilol on insulin resistance in high-fructose, high-fat diet (HFrHFD) - fed mice and the implication of the β-arrestin2 pathway. The acute effect of carvedilol (10mg/kg, i.p.) on glucose tolerance and hepatic lipid signaling in normal and insulin resistant mice was investigated. Then, the chronic effect of carvedilol on insulin resistance and dyslipidemia in HFrHFD-fed mice was examined. Changes in β-arrestin2 and its downstream signals in liver, skeletal muscle, and adipose tissue were measured. This involved measuring phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) levels and protein kinase B (AKT) activity. Carvedilol acutely reduced fasting blood glucose levels in both normal and insulin resistant mice without significantly affecting the glucose tolerance. These acute effects were associated with increased hepatic PIP2 but decreased hepatic DAG levels. Chronic administration of carvedilol significantly ameliorated insulin resistance and dyslipidemia in HFrHFD-fed mice. These chronic effects were associated with increased β-arrestin2, PIP2, and AKT activity levels but decreased DAG levels in the classical insulin target tissues. In conclusion, carvedilol acutely maintains glucose homeostasis and chronically ameliorates insulin resistance and dyslipidemia in HFrHFD-fed mice. The insulin sensitizing effects of carvedilol are highly correlated with the upregulation of β-arrestin2 pathway.

Evaluation of therapeutic effect of Premna herbacea in diabetic rat and isoverbascoside against insulin resistance in L6 muscle cells through bioenergetics and stimulation of JNK and AKT/mTOR signaling cascade

BackgroundPremna herbacea Roxb., a perennial herb is well documented for its therapeutic uses among the traditional health care-givers of Assam, India. Scientific validation on the traditional use of the medicinal plant using modern technology may promote further research in health care. PurposeThis study evaluates the therapeutic potential of methanolic extract of P. herbacea (MEPH) against type 2 diabetes mellitus (T2DM) and its phytochemical(s) in ameliorating insulin resistance (IR), thereby endorsing the plant bioactives as effective anti-hyperglycemic agents. MethodsThe anti-diabetic potential of the plant extract was explored both in L6 muscle cells and high fructose high fat diet (HF-HFD) fed male Sprague Dawley (SD) rats. Bioactivity guided fractionation and isolation procedure yielded Verbascoside and Isoverbascoside (ISOVER) as bioactive and major phytochemicals in P. herbacea. The bioenergetics profile of bioactive ISOVER and its anti-hyperglycemic potential was validated in vitro by XFe24 analyzer, glucose uptake assay and intracellular ROS generation by flourometer, FACS and confocal microscopy. The potential of ISOVER was also checked by screening various protein markers via immunoblotting. ResultsMEPH enhanced glucose uptake in FFA-induced insulin resistant (IR) L6 muscle cells and decreased elevated blood glucose levels in HF-HFD fed rats. Isoverbascoside (ISOVER) was identified as most bioactive phytochemical for the first time from the plant in the Premna genus. ISOVER activated the protein kinase B/AMP-activated protein kinase signaling cascades and enhanced glucose uptake in IR-L6 muscle cells. ISOVER decreased the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) and increased that of mammalian target of rapamycin (mTOR), thereby attenuating IR. However, molecular docking revealed that ISOVER increases insulin sensitivity by targeting the JNK1 kinase as a competitive inhibitor rather than mTOR. These findings were further supported by the bioenergetics profile of ISOVER. ConclusionThis study for the first time depicts the functional properties of ISOVER, derived from Premna herbacea, in ameliorating IR. The phytochemical significantly altered IR with enhanced glucose uptake and inhibition of ROS through JNK-AKT/mTOR signaling which may pave the way for further research in T2DM therapeutics.

Effect of Aronia melanocarpa fruit juice on carrageenan-induced paw edema in metabolic syndrome rats

INTRODUCTION: Chronic, low-grade inflammation plays a critical role in the pathogenesis of the metabolic syndrome (MS). Aronia melanocarpa fruits are rich in biologically active compounds—polyphenols, which possess a variety of health benefits including an anti-inflammatory effect. AIM: The aim of this article is to evaluate the effect of polyphenol-rich Aronia melanocarpa fruit juice (AMFJ) on carrageenan-induced acute inflammation in rats with diet-induced MS. MATERIALS AND METHODS: Forty male Wistar rats were included in the experiment. They were allocated into 4 groups: MS, MS+AMFJ 2.5 , MS+AMFJ 5 , and MS+AMFJ 10, all receiving high-fat high-fructose diet and 10% fructose in the drinking water for 10 weeks. The MS group served as a control and was treated daily with distilled water orally, while the other groups received AMFJ at doses of 2.5 mL/kg, 5 mL/kg, and 10 mL/kg, respectively. At the end of the experiment, carrageenan was injected in the left hind paw in order to induce acute inflammation. Paw edema was evaluated with plethysmometer on the 30 th min and 1 st , 2 nd , 3 rd , 4 th , and 5 th hour after the injection. RESULTS: In the MS group, the carrageenan-induced paw edema increased gradually with time reaching the highest value on the 5 th hour. A decrease throughout the whole 5-hour period was observed in groups treated with AMFJ, the effect being most pronounced and statistically significant in MS+AMFJ 5 group on the 2 nd and 3 rd hour. CONCLUSION: Aronia melanocarpa fruit juice treatment in rats with MS resulted in a decrease in the carrageenan-induced paw inflammation. The anti-inflammatory effect might be attributed to the polyphenols in AMFJ.

Effect of Probiotic Supplementation on Sprague Dawley Rat Liver Histopathology Fed by High Fat High Fructose Diet

Background: Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease burden worldwide. The gastrointestinal microbiota has a close relationship with the liver as the liver is most exposed to intestinal bacteria. Microbial manipulation is a potential and effective therapy as an alternative in the management of NAFLD/NASH. It has been found that probiotics prevent NAFLD/NASH. However, the study about the protective effect of probiotics on NAFLD/NASH is still limited. Objective: The objective of this study is to evaluate the effect of probiotics on liver histopathology Sprague Dawley rats which given high-fat high fructose (HFHFr) dietMethods: This study is a murine-model post-test-only control study group design. The samples were 21 Sprague Dawley male rats in 7 – 8 weeks of age and were divided into three groups. The Control Group (C) was provided with a standard chow diet for eight weeks. The Non-Probiotic (NP) group was given a High-Fat High Fructose (HFHFr) diet for eight weeks. The Probiotic group (P) was given a HFHFr diet for eight weeks, and a combination of HFHFr and probiotic supplementation consisted of Lactobacillus acidophilus, Bifidobacterium longum, and Streptococcus thermophilus for the next eight weeks. Histopathological samples were obtained from liver biopsy to assess steatosis, NAFLD activity score (NAS), and fibrosis stages. Wilcoxon test was done to analyze body weight before and after treatment. We analyzed the difference in histopathological results using the Mann-Whitney test.Results: We found a significant difference in NAFL and NAS Score between NP and P group. The P group was shown to have lower trends for NAFLD and NASH than the NP group, but not for fibrosis. There is no significant difference between pre and post-test body weight. Conclusion: Probiotics supplementation has a protective effect on liver histopathology against disturbances caused by the HFHFr diet.

Accelerated developmental adipogenesis programs adipose tissue dysfunction and cardiometabolic risk in offspring born to dams with metabolic dysfunction.

This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females (P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Hetdb dams (P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.

Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation.

Since westernized diet-induced insulin resistance is a risk factor in Alzheimer’s disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β (Aβ)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1β, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.

Etlingera elatior (Jack) R.M, Sm Containing Diet Normalizes Some Metabolic Syndrome Markers due to High-fat High-fructose Diet in Wistar Rats

Background: Etlingera elatior (Ee) contains phytochemical compounds that are rich in antioxidants, which may reduce several biochemical markers of metabolic syndrome (MetS). Objective: We aimed to study the effect of fresh Etlingera elatior (FEe) and steamed Etlingera elatior (SEe) as a part of rat diet on body weight, serum lipid, and malondialdehyde (MDA) level in Wistar rats with MetS induced by a high-fat, high-fructose diet. Methods: Our research was a true experimental randomized control group design with pre- and post-test. A total of 24 male Wistar rats were divided randomly into the following four groups: 1) Control, fed standard rat diet during the whole duration of the study, 2) HFFr-Sd, fed high-fat high- -fructose (HFFr) diet for 29 days, followed by 29 days of the standard diet, 3) HFFr-FEe, fed HFFr diet for 29 days, followed by 29 days of a standard diet containing 33.3% FEe, and 4) HFFr-SEe, fed HFFr diet for 29 days, followed by 29 days of a standard diet containing 33.3% SEe. The HFFr diet was given at 15 g/day along with fructose drink (20% pure fructose) at 100 ml/day. The diets in each group after the MetS induction period are referred to as intervention diets. Data at the end of HFFr (pre) and intervention diets (post) were analyzed by paired t-test. The data among groups were analyzed by one-way analysis of variance followed by post hoc test. Results: HFFr diet for 29 days induced MetS in Wistar rats fulfilling the criteria of obesity (Lee Index), hypertriglyceridemia, and decreased high-density lipoprotein cholesterol (HDL-C). Also, there was a significant increase in serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and MDA level (p &lt; 0.05). Feeding a diet containing FEe or SEe can significantly reduce body weight, serum triglyceride, total cholesterol, LDL-C, and MDA, and increase HDL-C levels (p &lt; 0.05). The effect of FEe was more pronounced in ameliorating body weight and lipid profile than SEe. Conclusion: Fresh Ee and Steamed Ee can ameliorate obesity, dyslipidemia, and oxidative stress in MetS Wistar rats induced by a high-fat, high-fructose diet. It suggests that dietary Ee accounting for one-third of daily standard diet can assist in normalizing some MetS markers in rats.

Melatonin induces Nrf2-HO-1 reprogramming and corrections in hepatic core clock oscillations in Non-alcoholic fatty liver disease.

Melatonin pleiotropically regulates physiological events and has a putative regulatory role in the circadian clock desynchrony-mediated Non-alcoholic fatty liver disease (NAFLD). In this study, we investigated perturbations in the hepatic circadian clock gene, and Nrf2-HO-1 oscillations in conditions of high-fat high fructose (HFHF) diet and/or jet lag (JL)-mediated NAFLD. Melatonin treatment (100µM) to HepG2 cells led to an improvement in oscillatory pattern of clock genes (Clock, Bmal1, and Per) in oleic acid (OA)-induced circadian desynchrony, while Cry, Nrf2, and HO-1 remain oblivious of melatonin treatment that was also validated by circwave analysis. C57BL/6J mice subjected to HFHF and/or JL, and treated with melatonin showed an improvement in the profile of lipid regulatory genes (CPT-1, PPARa, and SREBP-1c), liver function (AST and ALT) and histomorphology of fatty liver. A detailed scrutiny revealed that hepatic mRNA and protein profiles of Bmal1 (at ZT6) and Clock (at ZT12) underwent corrective changes in oscillations, but moderate corrections were recorded in other components of clock genes (Per1, Per2, and Cry2). Melatonin induced changes in oscillations of anti-oxidant genes (Nrf2, HO-1, and Keap1) subtly contributed in the overall improvement in NAFLD recorded herein. Taken together, melatonin induced reprograming of hepatic core clock and Nrf2-HO-1 genes leads to an improvement in HFHF/JL-induced NAFLD.

Vitamin D and rosuvastatin obliterate peripheral neuropathy in a type-2 diabetes model through modulating Notch1, Wnt-10α, TGF-β and NRF-1 crosstalk

AimsVitamin D and rosuvastatin are well-known drugs that mediate beneficial effects in treating type-2 diabetes (T2D) complications; however, their anti-neuropathic potential is debatable. Hence, our study investigates their neurotherapeutic potential and the possible underlying mechanisms using a T2D-associated neuropathy rat model. Main methodsDiabetic peripheral neuropathy (DPN) was induced with 8 weeks of administration of a high fat fructose diet followed by a single i.p. injection of streptozotocin (35 mg/kg). Six weeks later, DPN developed and rats were divided into five groups; viz., control, untreated DPN, DPN treated with vitamin D (cholecalciferol, 3500 IU/kg/week), DPN treated with rosuvastatin (10 mg/kg/day), or DPN treated with combination vitamin D and rosuvastatin. We determined their anti-neuropathic effects on small nerves (tail flick test); large nerves (electrophysiological and histological examination); neuronal inflammation (TNF-α and IL-18); apoptosis (caspase-3 activity and Bcl-2); mitochondrial function (NRF-1, TFAM, mtDNA, and ATP); and NICD1, Wnt-10α/β-catenin, and TGF-β/Smad-7 pathways. Key findingsTwo-month treatment with vitamin D and/or rosuvastatin regenerated neuronal function and architecture and abated neuronal inflammation and apoptosis. This was verified by the inhibition of the neuronal content of TNF-α, IL-18, and caspase-3 activity, while augmenting Bcl-2 content in the sciatic nerve. These treatments inhibited the protein expressions of NICD1, Wnt-10α, β-catenin, and TGF-β; increased the sciatic nerve content of Smad-7; and enhanced mitochondrial biogenesis and function. SignificanceVitamin D and/or rosuvastatin alleviated diabetes-induced neuropathy by suppressing Notch1 and Wnt-10α/β-catenin; modulating TGF-β/Smad-7 signaling pathways; and enhancing mitochondrial function, which lessened neuronal degeneration, demyelination, and fibrosis.

Pioglitazone Enhances β-Arrestin2 Signaling and Ameliorates Insulin Resistance in Classical Insulin Target Tissues

Introduction: Pioglitazone is a thiazolidinedione oral antidiabetic agent. This study aimed to investigate the effects of pioglitazone as insulin sensitizer on β-arrestin2 signaling in classical insulin target tissues. Methods: Experiments involved three groups of mice; the first one involved mice fed standard chow diet for 16 weeks; the second one involved mice fed high-fructose, high-fat diet (HFrHFD) for 16 weeks; and the third one involved mice fed HFrHFD for 16 weeks and received pioglitazone (30 mg/kg/day, orally) in the last four weeks of feeding HFrHFD. Results: The results showed significant improvement in the insulin sensitivity of pioglitazone-treated mice as manifested by significant reduction in the insulin resistance index. This improvement in insulin sensitivity was associated with significant increases in the β-arrestin2 levels in the adipose tissue, liver, and skeletal muscle. Moreover, pioglitazone significantly increased β-arrestin2 signaling in all the examined tissues as estimated from significant increases in phosphatidylinositol 4,5 bisphosphate and phosphorylation of Akt at serine 473 and significant decrease in diacylglycerol level. Conclusion: To the best of our knowledge, our work reports a new mechanism of action for pioglitazone through which it can enhance the insulin sensitivity. Pioglitazone increases β-arrestin2 signaling in the adipose tissue, liver, and skeletal muscle of HFrHFD-fed mice.

Effect of high-fat high fructose diet and carbon tetrachloride on high sensitivity C reactive protein (hsCRP) levels male Wistar rat

Background: The consumption of a high-fat diet affects fat metabolism in the body, and it gets progressively worse by adding high fructose to the diet. Similarly, the chemical compound carbon tetrachloride (CCl4) can cause toxic effects in multiple organs. High sensitivity C reactive protein (hsCRP) is a micro-inflammatory marker used as a primary preventive tool against several diseases. This study aimed to determine the impact of giving a high-fat, high-fructose diet (HFHFD) and CCl4 on hsCRP levels of Wistar rats.Methods: An experimental study among 24 male Wistar rats aged 8-12 weeks divided into four groups. Rats were fed an HFHFD and were either administered CCl4 biweekly (0.08 mL/kg, peritoneal) or not. The other two groups were fed with standard chow meal with CCl4 injection, and the un-injected group stands as a control group. All groups were monitored for eight weeks, and serum parameters were examined. Data were analyzed using SPSS version 17 for Windows. P-value &lt;0.05 was significant.Results: The intake of a high fat and high-fructose diet for eight weeks was proven to have higher levels of hsCRP than those without the diet. Similar to the administration of 0.8 ml/kg peritoneal CCl4 biweekly shown to have higher levels of hsCRP compared to the control group. This study also showed increased body weight except for the group that received a standard meal and CCl4 peritoneal injection.Conclusion: High-fat high fructose diet and carbon tetrachloride had a significant effect on hsCRP level.

Gut Microbiota Induced by Pterostilbene and Resveratrol in High-Fat-High-Fructose Fed Rats: Putative Role in Steatohepatitis Onset.

Resveratrol and its 2-methoxy derivative pterostilbene are two phenolic compounds that occur in foodstuffs and feature hepato-protective effects. This study is devoted to analysing and comparing the metabolic effects of pterostilbene and resveratrol on gut microbiota composition in rats displaying NAFLD induced by a diet rich in saturated fat and fructose. The associations among changes induced by both phenolic compounds in liver status and those induced in gut microbiota composition were also analysed. For this purpose, fifty Wistar rats were distributed in five experimental groups: a group of animals fed a standard diet (CC group) and four additional groups fed a high-fat high-fructose diet alone (HFHF group) or supplemented with 15 or 30 mg/kg bw/d of pterostilbene (PT15 and PT30 groups, respectively) or 30 mg/kg bw/d of resveratrol (RSV30 group). The dramatic changes induced by high-fat high-fructose feeding in the gut microbiota were poorly ameliorated by pterostilbene or resveratrol. These results suggest that the specific changes in microbiota composition induced by pterostilbene (increased abundances of Akkermansia and Erysipelatoclostridium, and lowered abundance of Clostridum sensu stricto 1) may not entirely explain the putative preventive effects on steatohepatitis.

Effect of black garlic on visceral fat, oxidative stress and insulin resistance in nonalcoholic fatty liver disease rats

Purpose This paper aims to determine the effect of black garlic (BG) on visceral fat, oxidative stress and insulin resistance (IR) compared with metformin and vitamin E in nonalcoholic fatty liver disease (NAFLD) rats. Design/methodology/approach A randomized post-test only design with control group was used in this study. Rats were given high-fat fructose diet enriched with 1.25% cholesterol and 0.5% cholic acid for eight weeks to induce NALFD condition. The administration of BG dose of 450 mg/200 gBW, 900 mg/200 gBW and 1350 mg/200 gBW with a comparative control of 45 mg/200 gBW of metformin and vitamin E of 9 IU/200 gBW were given for four weeks via oral gavage to reduce visceral fat, oxidative stress and improve IR. Statistical analyses were performed to examine differences between groups with one-way analysis of variance and nonparametrics test. Findings Rats given with three different doses of BG for four weeks did not reduce body weight from 244 ± 4.4 to 284 ± 4.6 g, 242 ± 2.5 to 272 ± 3.1 g and 240 ± 2.4 to 270 ± 3.6 g, respectively, but significantly reduced visceral fat (p = 0.001) on BG groups with 3.7 ± 1.3, 2.7 ± 0.7 and 1.8 ± 0.6 g, respectively. BG improved oxidative stress (p = 0.001) with malondialdehyde level 5.1 ± 0.2, 3.0 ± 0.06 and 2.3 ± 0.06 ng/mL, respectively, but did not better than vitamin E group 1 ± 0.03 ng/mL. Significant (p = 0.001) improvement on insulin resistance with homeostatic model assessment IR in BG groups were 5.3 ± 0.1, 4.4 ± 0.1 and 4 ± 0.1, respectively, but not as good as metformin group 3.7 ± 0.1. Research limitations/implications Based on the experiment, there are several limitations including small sample size, performed on animal models in a relatively short time, did not examine organosulfurs compound (OSC) content of BG specifically and OSC affects metabolism in NAFLD remains unclear and will require further investigation. Practical implications BG is a functional food made from heated fresh garlic owing to the Maillard reaction and the organosulfur compounds as antioxidants. The higher the dose of BG, the greater the improvement in visceral fat, oxidative stress and IR in model NAFLD rats. Social implications NAFLD is a liver disorder caused by excessive fat and energy intake, the treatment strategies among others through diet modification. Originality/value In model NAFLD rats, BG administration improved NALFD markers but did not better rather than the metformin and vitamin E result.

Genistein and exercise treatment reduced NASH related HDAC3, IL-13 and MMP-12 expressions in ovariectomized rats fed with high fat high fructose diet

Background and aimGenistein (GEN) and exercise (Ex) may be regarded as an alternative treatment for non-alcoholic steatohepatitis (NASH). However, the mechanisms behind their therapeutic effects in NASH are not well-understood. Experimental procedureThis study investigated the roles of histone deacetylase (HDAC)3 and interleukin-(IL-)13 in the NASH model of ovariectomized (OVX) rats fed with high fat high fructose (HFHF) diet. Results and conclusionNine weeks after being fed with HFHF diet, severe NASH pathology with mild fibrosis were seen along with an increase in HDAC3, IL-13 and matrix metalloelastase (MMP-12) expressions in OVX rats. Five weeks of either GEN or Ex treatments abrogated the increase in both HDAC3 and IL-13 expressions in OVX rats fed with HFHF diet and ameliorated NASH features, liver fibrosis and MMP-12 expression. The combination of Gen and Ex, however, did not provide additional benefits on NASH features in OVX rats fed with HFHF diet. These results suggested that GEN and Ex treatments improved HFHF diet induced NASH in OVX rats through the suppression of HDAC3, IL-13 and MMP-12 expression.

Hepatocyte‐specific Overexpression of Fatty Acid Desaturase 1 Improves Insulin Signaling and ameliorates hypertriglyceridemia in Male Rat

Objective Decreased fatty acid desaturase 1 (Fads1) activity results in the accumulation of saturated fat, which contributes to the development of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine whether hepatic overexpression of Fads1 attenuates a dietary high-fat high-fructose (HFHF)-induced metabolic phenotype. Methods Hepatocyte-specific overexpression of Fads1 was achieved via the tail vein injection of recombinant adeno-associated virus (AAV) serotype 8 containing an albumin promoter with rat Fads1 sequence. Blank vectors served as controls. Male weanling Sprague-Dawley rats were assigned to five groups and fed with chow diet, low-fat high-fructose diet with AAV8 blank control (LFHF-AAV8-Blank), LFHF-AAV8-Fads1, high-fat high-fructose diet with AAV8 blank control (HFHF-AAV8-Blank), or HFHF-AAV8-Fads1 (n=8 rats/group) for 8 weeks. Metabolic phenotypes were characterized, including body weight, level of hepatic steatosis, glucose and insulin tolerance tests (GTT, ITT). Liver, skeletal muscle and adipose tissue insulin signaling were examined by western blot. Results Hepatocyte-specific overexpression of Fads1 significantly decreased body weight gain and improved glucose tolerance, but not hepatic steatosis, in LFHF-fed rats. These effects were not evident in HFHF-fed rats. On the contrary, white adipose tissue weight was markedly reduced in HFHF-AAV8-Fads1 rats compared to HFHF-AAV8-blank control rats, and to a lesser extent in LFHF rats. Both LFHF-AAV8-Fads1 and HFHF-AAV8-Fads1 rats displayed decreased fasting plasma triglycerides and increased plasma free fatty acids compared to their AAV8-blank control rats, and this was associated with upregulation of adipose tissue hormone sensitive lipase (HSL). While phosphorylated Akt (p-Akt) expression was downregulated, phosphorylated glycogen synthase kinase 3β (GSK-3β) was upregulated by both LFHF and HFHF diet in skeletal muscle, these alterations were not evident in the liver and adipose tissue. Moreover, decreased expression of p-Akt in skeletal muscle was partially restored in HFHF-AAV8-Fads1 rats, but not in LFHF-AAV8-Fads1 rats. Conclusion Our data demonstrated that hepatocyte-specific overexpression of Fads1 leads to the improvement of metabolic phenotypes in a diet- and tissue-specific manner, and this was associated with improved insulin signaling in skeletal muscle. The underlying mechanism(s) need further investigation.

The effect of single clove Black garlic on the hemostasis status and lipid profile in male Sprague Dawley rats with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) patients have alteration in hemostasis components. Thus, including excess expression of plasminogen activator inhibitor-1 (PAI-1), causing fibrinolysis disorders; the majority of these patients are hypercoagulable state prone to thrombosis. Some evidence suggests that garlic and garlic supplements have antithrombotic and anti-inflammatory properties. Besides, garlic stimulates fibrinolytic activity and normalizes plasma lipid imbalances. Black garlic is processed garlic that is produced through natural aging at a controlled temperature (70 °C) and high humidity (90%) for several days, without other additives. This study aimed to prove the effect of single clove black garlic (SCBG) (Allium sativum Linn) on PAI-1 levels and lipid profiles of NAFLD rats induced by a high-fat fructose diet (HFFD) containing 1.25% cholesterol and 0.5% cholic acid.The rats were then divided into healthy control group (K1+); NAFLD control group without treatment (K2+); 0.9 mg simvastatin treatment group (K1-); 45 mg metformin treatment group (K2-); SCBG 450 mg per 200g BW (X1); 900 mg per 200 g BW (X2); and 1350 mg per 200 g BW (X3). All treatments were administered for 4 weeks via oral gavage. As a result, significant differences in PAI-1 levels and lipid profiles between groups after the administration (p = 0.001) were noted and also by simvastatin and metformin, respectively. There was a correlation between PAI-1 and lipid profile of SCBG treatment. In conclusion, the administration of SCBG (1350 mg per 200 g BB per day) for 4 weeks had a significant effect on PAI-1 levels, and the lipid profiles in Sprague Dawley rats modeled NAFLD (p = 0.001). SCBG has provided benefits that can be useful in the management of NAFLD but it’s not equivalent to medicine.

Protective effects of HIIT vs. CET exercise training on high-fat-high-fructose diet-induced hyperglycemia, hyperlipidemia, and histopathology of liver in rats: regulation of SIRT1/PGC-1α

Disruption of the function of sirtuin1 (SIRT1) has been reported to link with diabetes and metabolic disorders. The aim of this study was to investigate the effect of a modified high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) or continuous endurance training (CET) program on Sirt1 and PGC-1α mRNA gene expression in hepatocytes of high-fat/high-fructose diet-induced diabetes in rats. Twenty-eight male Wistar rats (220 ± 20 g) were randomly divided into four groups of non-diabetic (NDC), diabetic control (received high fat high-fructose diet (HFHFD-DC)), CET (HFHFD-CET), and HIIT (HFHFD-HIIT). Diabetes was induced by feeding rats a high-fat (30%) high-fructose (20%) diet for 25 weeks. Following confirmed hyperglycemia, both HFHFD-CET (60–65% Vo2max) and HFHFD-HIIT (85–90% Vo2max) rats underwent treadmill exercise for 30 min, 5 days/week at 10 m/min for 8 weeks. Thereafter, blood and liver samples were obtained for biochemical studies. For histological analysis, the liver was fixed in 10% formalin, embedded in paraffin, and sectioned (5 μm thickness) for H&E staining. SIRT-1 and PGC-1α mRNA expression were measured by RT-PCR from the liver sample (frizzed sample). All data were presented as mean ± standard error mean and compared the differences by one-way analysis of variances. The alpha level was set at 0.05 (p < 0.05) for statistical difference. The results show that HIIT was more effective than CET to reduce vesicular steatosis. HIIT significantly enhanced the expression of SIRT-1 compared to the HFHFD-DC group (fold change: 1.47, p < 0.047). However, HIIT decreased PGC-1α expression compared to the HFHFD-DC group, but it was not significant (fold change: 1.32 and p < 0.247). HIIT was more effective than CET in SIRT-1 expression augmentation in high-fat, high-fructose diabetic rats which suggests a possible treatment strategy in the context of type 2 diabetes.

Alleviation of Liver Dysfunction, Oxidative Stress, and Inflammation Underlines the Protective Effects of Polysaccharides from Cordyceps cicadae on High Sugar/High Fat Diet‐Induced Metabolic Syndrome in Rats

This study investigated the protective effects of two polysaccharides (CPA-1 and CPB-2) from Cordyceps cicadae against high fructose/high fat diet (HF/HFD) induced obesity and metabolic disorders in rats. Rats were either fed with normal diet or HF/HFD and treated with CPA-1 and CPB-2 (100 and 300 mg/kg) for 11 weeks. Administration of CPA-1 and CPB-2 significantly and dose dependently reduced body and liver weight, insulin and glucose tolerance, serum insulin and glucose levels. Furthermore, serum and hepatic lipid profiles, liver function enzymes and proinflammatory cytokines (TNF-α, IL-1β and IL-6) were markedly reduced. Additionally, CPA-1 and CPB-2 treatment alleviated hepatic oxidative stress by reducing lipid peroxidation level (MDA) and upregulating glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) activities as well as ameliorated histological alterations through the reduction of hepatic lipid accumulation. These results suggested that the polysaccharides from C. cicadae showed protective effects against HF/HFD induced metabolic disturbances and may be considered as a dietary supplement for treating obesity.

High-fructose diet initially promotes increased aortic wall thickness, liver steatosis, and cardiac histopathology deterioration, but does not increase body fat index.

Background: Dietary fats and fructose have been responsible for inducing obesity and body tissues damage due to the consequence of metabolic syndrome through several mechanisms. The body fat index (BFI) is one of the anthropometric measures used to detect obesity in rats. This study aims to examine the correlation between high-fat high-fructose diet and liver steatosis cell count, early atherosclerosis characteristics, and body fat index (BFI) in Sprague Dawley rats.Design and methods: This was an experimental design using 2 groups of 12-weeks-old Sprague Dawley (SD) rats. The control group received a standard diet and tap water beverages for 17 weeks. The intervention group was fed with high-fat diet from modified AIN 93-M and additional 30% fructose drink. We analyzed the foam cell count, aortic wall thickness, cardiac histopathology, and liver steatosis cell count after the sacrifice process.Results: The rats in the intervention group had a higher aortic wall thickness, liver steatosis, and foam cell count (+125%, p<0.01; +317%, p<0.01 and +165%, p<0.01 respectively) compared to the control group. The intervention group also showed higher mononuclear inflammatory and hypertrophic cell count. A significant positive correlation was found between dietary fructose with premature atherosclerosis by increasing foam cell count (r=0.66) and aortic wall thickness (r=0.68). In addition, 30% dietary fructose increased liver steatosis (r=0.69) and mononuclear inflammatory cardiac cell count (r=0.61). Interestingly, the intervention had no effect on the body fat index (p>0.5; r=0.13).Conclusions: Dietary fat and fructose consumption for 17 weeks promotes atherosclerosis, liver steatosis, and cardiac histopathology alteration without increasing BFI.Significance for public healthObesity is a major health problem that is a powerful inducer of non-communicable disease (NCD) both in the national and global level of the human population age groups. Based on this study, consumption of fructose also poses an increased risk in developing metabolic syndrome, which differs from the current understanding of dominantly caused by excessive intake of fat. Furthermore, high fructose consumption promotes early signs of cardiovascular and liver disease without significant manifestation in anthropometry characteristics. It is believed that these results are important and will give readers a broader view on combating obesity epidemics from a dietary and nutritional perspective, which may also contain additional reference for nutrition education or dietary advice for the prevention of obesity.

Methanolic Extract of Lysimachia Candida Lindl. Prevents High-Fat High-Fructose-Induced Fatty Liver in Rats: Understanding the Molecular Mechanism Through Untargeted Metabolomics Study.

Fatty liver is one of the most common metabolic syndrome affecting the global population. Presently, limited treatment modalities with symptomatic approach are available for alleviating fatty liver. Traditional and herbal treatment modalities have shown evidence to improve the disease pathology. In the present research work, evaluation of a selected medicinal plant Lysimachia candida Lindl. was carried out to investigate its beneficial effects on fatty liver disease in rats. Male Sprague Dawley (SD) rats were fed with high-fat high-fructose diet to induce fatty liver phenotypes. After induction for 15 weeks, methanolic extract of Lysimachia candida Lindl. (250 mg/kg b. w. p. o.) was administrated to the rats daily for the next 17 weeks. Blood samples were collected at different time points to analyze fasting blood glucose levels and relevant biochemical parameters important for the assessment of metabolic disease phenotypes. Liquid chromatography-mass spectrometry (LC-MS) based metabolomics was done to study the dynamics of metabolic changes in the serum during disease progression and how the medicinally important plant extract treatment reversed the metabolic diseases. Multivariate data analysis approaches have been employed to understand the metabolome changes and disease pathology. This study has identified the interplay of some metabolic pathways that alter the disease progression and their reversal after administration of the plant extract. Different group of metabolites mainly bile acids, fatty acids, carnitines, and their derivatives were found to be altered in the diseased rats. However, all the metabolites identified between control and disease groups are mainly related to lipid metabolism. The results depict that the treatment with the above-mentioned plant extract improves the regulation of aberrant lipid metabolism, and reverses the metabolic syndrome phenotype. Therefore, the present study reveals the potential mechanism of the herbal extract to prevent metabolic syndrome in rats.