Metabolic Syndrome In Fructose-fed Rats Research Articles

Beneficial effects of non-quinazoline α1-adrenolytics on hypertension and altered metabolism in fructose-fed rats. A comparison with prazosin

Background and aimsMetabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate NO/cGMP/K+ pathway, ameliorates metabolic syndrome in fructose-fed rats. As reference compound prazosin was used. Methods and resultsMale rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects. Conclusionsα1–adrenoceptor blockade, endothelial protection, TNF-α suppressing and antioxidant activity together with favorable pharmacokinetic parameters determines high efficacy of MH-76, leading to the effective improvement of hemodynamic and metabolic disturbances in metabolic syndrome. The use of non-quinazoline, multiple-targeted α1-blockers may be an interesting option for treatment of hypertension with metabolic complications.

Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats.

Renin–angiotensin system in visceral fat plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. However, the effects of renin inhibition on visceral adiposity in metabolic syndrome are not fully investigated. We investigated the effects of renin inhibition on visceral adiposity in fructose-fed rats. Male Wistar–Kyoto rats were divided into 4 groups for 8-week experiments: Group Con (standard chow diet), Group Fru (high-fructose diet; 60% fructose), Group FruA (high-fructose diet and concurrent aliskiren treatment; 100 mg/kg body weight [BW] per day), and Group FruB (high-fructose diet and subsequent, i.e. 4 weeks after initiating high-fructose feeding, aliskiren treatment; 100 mg/kg BW per day). The high-fructose diet induced metabolic syndrome, increased visceral fat weights and adipocyte sizes, and augmented angiotensin II (Ang II), NADPH oxidase (NOX) isoforms expressions, oxidative stress, and dysregulated production of adipocytokines from visceral adipose tissues. Concurrent and subsequent aliskiren administration ameliorated metabolic syndrome, dysregulated adipocytokines, and visceral adiposity in high fructose-fed hypertensive rats, and was associated with reducing Ang II levels, NOX isoforms expressions and oxidative stress in visceral fat tissues. Therefore, this study demonstrates renin inhibition could improve metabolic syndrome, and reduce Ang II levels and oxidative stress in visceral fat tissue in fructose-fed rats, and suggests that visceral adipose Ang II plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats.

Coadministration of black seeds and turmeric shows enhanced efficacy in preventing metabolic syndrome in fructose-fed rats.

Among noncommunicable diseases, metabolic syndrome (MS), a cluster of metabolic disorders including obesity, hyperglycemia, hyperlipidemia and hypertension, is highly prevalent in modern society. Its management requires lifestyle modifications and/or the life-long use of multiple medications, hence demanding development of safe alternative remedies. This study was aimed to establish the efficacy of combined use of black seeds and turmeric using fructose-fed rat model of MS. The high-performance liquid chromatographic fingerprints of turmeric and black seeds showed the presence of curcumin and thymoquinone, respectively, as their major constitutes. Different doses of black seeds and turmeric, individually and in combination, were administered to fructose-fed rats for up to 6 weeks representing characteristic features of MS. At 3 weeks of the treatment, black seeds and turmeric lowered (P < 0.01) high blood pressure and low-density lipoprotein cholesterol, respectively, whereas their coadministration reduced (P < 0.01) both high blood pressure and hypertriglyceridemia. At 6 weeks, the coadministration of both herbs, at half the doses of individual herbs, was the most effective (P < 0.001) in preventing hypertension, hyperglycemia, dyslipidemia, hyperinsulinemia, and endothelial dysfunction than the individual herbs. This study demonstrates the therapeutic superiority of the combination of black seeds and turmeric at low doses over individually tested herbs, in improving features of MS.

고과당식이 랫드모델에서 홍삼과 상엽 혼합투여에 의한 대사증후군 개선효과

ABSTRACT Objectives : Korean red ginseng and Morus alba L. are used as a traditional treatment for diabetes. This study was designed to elucidate whether combination with Korean red ginseng and Morus alba L. (MPM) ameliorates metabolic syndrome in fructose-fed rats. Methods : Animals were divided into four groups; Control receiving tap w ater, fructose-fed, rosiglitazone-treated fructose-fed rats, and MPM-treated fructo se-fed rats both receiving supplemented with 60% fructose (n=10). The MPM or rosiglitazone groups initially received a high-fructose (HF) diet alone for 8 weeks, with supplementation with MPM or rosiglitazone occurring during the final 6 weeks. Results : MPM and rosiglitazone, synthetic PPARγ agonist, treatment signi ficantly prevented the increase in fasting serum glucose, leptin, triglyceride, and low density lipoprotein in the HF group when comparing with the control group. MPM and rosiglitazone also led to an increase in high density lipoprotein level in the HF group. The administration of MPM and rosiglitazone prevented th e development of the metabolic disturbances such as impaired glucose tolerance, and blood pressure. MPM sup pressed increased expressions of endothelin-1 (ET-1) in HF rat aorta. In addition, MPM significantly increased IR-β and PPAR-γ expression in muscle. Conclusions : Based on these results, we suggest that the administration of MPM improves metabolic syndrome through the alteration in lipid profiles and suppression of insulin resistant and blood pressure.Key words : Korean red ginseng, Morus alba, metabolic syndrome, hyperlipide mia, hypertension.

The metabolic syndrome of fructose-fed rats: Effects of long-chain polyunsaturated ω3 and ω6 fatty acids. V. Post-mortem findings

The present study deals with the possible effects of dietary ω3 and ω6 fatty acids upon the metabolic syndrome found in rats exposed for 8 weeks to a diet containing 64% (w/w) D-fructose instead of starch. Fructose-fed rats were found to display a modest increase in plasma albumin and protein concentration and more pronounced increases in plasma urea, creatinine, phospholipids, triglycerides and cholesterol concentrations, glycated hemoglobin concentration and liver contents of cholesterol, triglycerides and phospholipids. The plasma concentrations of HDL-cholesterol, calcium and iron were decreased, however, in the fructose-fed rats. In general, the partial substitution of sunflower oil by either safflower oil or salmon oil opposed the metabolic perturbations otherwise associated with the fructose-induced metabolic syndrome in the fructose-fed rats, with salmon oil demonstrating particular efficacy. Consideration is given to the possible biological determinants of these perturbations and their attenuation in rats exposed to safflower or salmon oil.

The metabolic syndrome of fructose-fed rats: Effects of long-chain polyunsaturated ω3 and ω6 fatty acids. VII. Oxidative stress

In the present study, the plasma concentration, and liver, heart, kidney, soleus muscle and visceral adipose tissue content of thiobarbituric acid reactive substrates (TBARS), carbonyl radicals, hydroperoxides and nitric oxide were measured in control rats exposed for 8 weeks to a diet containing 64% (w/w) starch and 5% sunflower oil and in animals fed a diet containing 64% D-fructose and 5% sunflower oil or 3.4% sunflower oil mixed with 1.6% safflower or salmon oil. Coherent measurements of the plasma concentrations or tissue contents of these metabolites revealed increases in TBARS, carbonyl radical and hydroperoxide levels and a decrease in nitric oxide levels in the 5% sunflower oil-fed rats. In the fructose-fed rats, the partial substitution of sunflower oil by either safflower or salmon oil minimized the changes. These findings provide further evidence in support of the favorable effects of the dietary supply of long-chain polyunsaturated ω6 and ω3 fatty acids upon the metabolic disturbances prevailing in the fructose-induced metabolic syndrome.

The metabolic syndrome of fructose-fed rats: Effects of long-chain polyunsaturated ω3 and ω6 fatty acids. VI. Further post-mortem investigations

The present study documents the increases in systolic arterial blood pressure, plasma leptin concentration and kidney proliferating cell nuclear antigen index, as well as the decreases in glutathione reductase, superoxide dismutase and catalase enzymatic activities in the liver, heart, kidney, soleus muscle and visceral adipose tissue homogenates of female rats exposed for 8 weeks to a diet containing 64% (w/w) D-fructose instead of 64% starch. In the fructose-fed rats, the partial substitution of sunflower oil by either safflower oil or salmon oil often opposed the fructose-induced changes in these variables. The present results, thus, extend to these functional, hormonal and enzymatic parameters the knowledge that the dietary supply of long-chain polyunsaturated ω6 fatty acids, mainly C18:2ω6, and long-chain polyunsaturated ω3 fatty acids opposes the undesirable features of the fructose-induced metabolic syndrome, with salmon oil demonstrating particular efficacy.

The metabolic syndrome of fructose-fed rats: Effects of long-chain polyunsaturated ω3 and ω6 fatty acids. IV. D-glucose metabolism by isolated pancreatic islets

The major aim of the present study was to search for changes of D-glucose metabolism in isolated pancreatic islets possibly involved in the alteration of their secretory response to the hexose, as observed when comparing rats exposed for 8 weeks to diets containing either starch and sunflower oil or fructose and sunflower oil, as well as rats exposed to diets containing fructose, sunflower oil and either salmon oil or safflower oil. The substitution of starch by fructose in the diet affected unfavourably D-glucose phosphorylation by the isolated islets. In the fructose-fed rats, there was a close parallelism between D-[5-³H]glucose utilization and the dietary ω3/ω6 fatty acid ratio. There was little to distinguish, however, between the four groups of rats in terms of D-[U-¹⁴C]glucose oxidation. The paired ratio between D-[U-¹⁴C]glucose oxidation and D-[5-³H]glucose utilization, which always increased as the concentration of the hexose was raised from 2.8 to 8.3 and 16.7 mM, was tightly related, in the fructose-fed rats, to the HOMA index for insulin resistance.

The metabolic syndrome of fructose-fed rats: Effects of long-chain polyunsaturated ω3 and ω6 fatty acids. III. Secretory behaviour of isolated pancreatic islets

In the present study, rats were exposed from the 8th week after birth and for the ensuing 8 weeks to diets containing either starch or fructose (64% w/w) and sunflower oil (5%). Two further groups of rats were exposed to the fructose-containing diet with substitution of part (1.6%) of the sunflower diet by an equal amount of either salmon oil rich in long-chain polyunsaturated ω3 fatty acids or safflower oil reach in long-chain polyunsaturated ω6 fatty acids. The insulin content of the islets and their secretory response to D-glucose (5.6, 8.3 and 16.7 mM), to the combination of D-glucose (5.6 mM) and D-fructose (10.0 mM) and to 2-ketoisocaproate (10.0 mM) were then measured. In the sunflower oil-fed rats, the dietary substitution of starch by fructose decreased basal insulin output, lowered the apparent Km for the insulinotropic action of D-glucose and altered the insulinotropic efficiency of the latter hexose relative to that of other nutrients. Some of these secretory perturbations were opposed by the enrichment of the diet in long-chain polyunsaturated fatty acids, especially ω3 fatty acids. It is proposed that these changes in B-cell secretory behaviour may be linked, in part at least, to both the apparent caloric efficiency of each diet, and hence to the regulation of the islet content in endogenous nutrients, and to alteration of insulin sensitivity considered as a major feature of the present animal model of metabolic syndrome.

The metabolic syndrome of fructose-fed rats: Effects of long-chain polyunsaturated ω3 and ω6 fatty acids. II. Time course of changes in food intake, body weight, plasma glucose and insulin concentrations and insulin resistance

The time course for changes in food intake, body weight, plasma glucose and insulin concentrations and HOMA index was monitored over a period of 8 weeks in rats exposed from the 8th week after birth to diets containing either starch or fructose and sunflower oil. In two further groups of rats exposed to the fructose-rich diet part of the sunflower oil was substituted by either salmon oil rich in long-chain polyunsaturated ω3 fatty acids or safflower oil rich in long-chain polyunsaturated ω6 fatty acids. Despite lower food intake, the gain in body weight was higher in fructose-fed rats than in starch-fed rats. The supplementation of the fructose-rich diet by either ω3 or ω6 fatty acids lowered both food intake and body weight gain. The measurements of plasma glucose and insulin concentrations, HOMA index and insulinogenic index performed after overnight starvation were in fair agreement with those recorded at the occasion of an intraperitoneal glucose tolerance test, with higher values for plasma glucose concentration and HOMA index in the fructose-fed rats exposed to the sunflower oil (with or without enrichment with ω6 fatty acids) than in the starch-fed rats exposed to the sunflower oil or fructose-fed rats exposed to a diet enriched with ω3 fatty acids. Such was also the case for the measurements of glycated albumin at sacrifice. Moreover, the insulinogenic index was lower in the fructose-fed rats with or without dietary enrichment in ω6 fatty acids than in the fructose-fed rats with dietary enrichment in ω3 fatty acids. The elucidation of the biochemical determinants of the later difference requires further investigations in isolated pancreatic islets.

The metabolic syndrome of fructose-fed rats: Effects of long-chain polyunsaturated ω3 and ω6 fatty acids. I. Intraperitoneal glucose tolerance test

The present series of experiments aim mainly at investigating the possible influence of changes in the com-position of dietary lipids (sunflower oil, salmon oil, safflower oil) upon the metabolic syndrome found in rats exposed to a fructose-rich diet. For purpose of comparison, a control group of rats received the sunflower oil diet with substitution of fructose by starch. An intraperitoneal glucose tolerance test, performed after overnight starvation fifty days after the start of the experiments at the 6th week after birth, indicated, as expected, impaired tolerance to glucose and deterioration of insulin sensitivity (HOMA index), without changes in the insulinogenic index, when comparing the fructose-fed rats to the starch-fed rats both exposed to the sunflower oil diet. In the fructose-fed rats, enrichment of the diet by long-chain polyunsaturated ω3 fatty acids supplied by salmon oil, a modest improvement of insulin sensitivity was opposed, in term of glucose homeostasis, by a decreased secretory response to glucose of insulin-producing cells. Last, in the fructose-fed rats, the partial substitution of sunflower oil by safflower oil rich in long-chain polyunsaturated ω6 fatty acids further deteriorated glucose homeostasis, with a higher mean HOMA index and a severe decrease of the insulinogenic index. These findings justify further investigations on such items as the time course for changes in metabolic and hormonal variables and both the metabolic and secretory responses of isolated pancreatic islets to selected nutrient secretagogues.

Aliskiren prevents and ameliorates metabolic syndrome in fructose-fed rats

IntroductionThe renin-angiotensin system plays a major role in the pathogenesis of metabolic syndrome. The objective of this study was to examine the effects of aliskiren, a direct renin inhibitor, on the metabolic syndrome of fructose-fed rats.Material and methodsMale Sprague-Dawley rats were divided into 4 groups (n = 6 for each group). Group Con: rats were fed a standard chow diet for 8 weeks, group Fru: rats were fed a high fructose diet (60% fructose) for 8 weeks, group FruA: rats were fed a high fructose diet and were co-infused with aliskiren (100 mg/kg/day), and group FruB: rats were treated as group Fru, but aliskiren was administered 4 weeks later. Systolic blood pressure (SBP), homeostasis model assessment-insulin resistance (HOMA-IR), and blood profiles were measured.ResultsBy the end of week 4 and 8 of a high fructose diet, SBP had increased significantly from 111 ±5 to 142 ±4 and 139 ±5 mmHg (p < 0.05), respectively. A high fructose diet significantly increased HOMA-IR from baseline (6.15 ±1.59) to 21.25 ±2.08 and 21.28 ±3.1 (p < 0.05) at week 4 and 8, respectively, and significantly induced metabolic syndrome. Concurrent aliskiren treatment prevented the development of hypertension and metabolic syndrome in fructose-fed rats. When fructose-induced hypertension was established, subsequent aliskiren treatment for 4 weeks reversed the elevated SBP and ameliorated metabolic syndrome. There were no significant differences in food, water intake, urine flow or body weight gain among groups.ConclusionsAliskiren not only prevents but also ameliorates metabolic syndrome in fructose-fed rats.

Effect of a Proanthocyanidin-Rich Extract from Longan Flower on Markers of Metabolic Syndrome in Fructose-Fed Rats

Recent evidence strongly suggests that oxidative stress due to redox imbalance is highly associated with metabolic syndrome. The objective of this study was to evaluate the effect of the supplementation of longan flower water extract (LFWE), which showed powerful antioxidative activity in vitro, on markers of metabolic syndrome in a fructose-fed rat model. Male Sprague-Dawley rats were randomly divided into four groups: group C, fed with standard Purina chow; group F, fed with high-fructose diet (HF) alone; group L, fed with HF plus LFWE 125 mg/kg bw per day by gavage; and group H, fed HF plus LFWE 250 mg/kg bw per day by gavage. The dietary manipulation lasted for 14 weeks. Results of our study showed that rats fed with HF resulted in oxidative stress and affected the antioxidant status including plasma thiobarbituric acid and liver antioxidant enzyme activity. Treatment with LFWE significantly augmented the antioxidant system. HF was able to cause insulin resistance and elevation of the blood pressure. The supplementation of LFWE ameliorated insulin resistance by enhancing the expression of insulin signaling pathway related proteins, including insulin receptor substrate-1 and glucose transporter 4. LFWE supplementation was also found to decrease systolic blood pressure. These findings indicate that longan flower water extract may improve the symptoms of metabolic syndrome in fructose-fed rats.

Alterations of nerve-growth factor and p75NTR expressions in urinary bladder of fructose-fed obese rats

The study investigated the effects of metabolic syndrome on urinary bladder nerve-growth factor (NGF) and p75(NTR) expression in fructose-fed obese rats. Age-matched male Wistar rats were divided into four groups; group I: normal control rats; group II: 6-week fructose-fed rats (FR); group III: 9-week FR; and group IV: 12-week FR. In vivo cystometry under anesthesia was performed. In vitro bladder NGF levels were measured by enzyme-linked immunosorbent assay (ELISA). Expressions of the mRNAs that encoded NGF and NGF receptor p75(NTR) in control and 9-week FR bladder were studied using the method of reverse transcription combined with polymerase chain reaction (RT-PCR). The three groups of FR showed significant increases in body weight, blood pressure, plasma glucose, insulin and triglyceride levels when compared to control rats. The bladder NGF levels in the 9-week and 12-week FR were significantly lower than the control (66.8+/-5.4, 49.4+/-7.1 and 95.2+/-6.5 pg/microg protein; p<0.05 and p<0.01 respectively, for n=8 in each group). The bladder emptying function was deteriorated in these two groups of FR as shown by the significantly increased residual volume and decreased emptying fraction. The mRNA expressions of bladder NGF and p75(NTR) in the 9-week FR were significantly decreased when compared to the control group (p<0.05 and p<0.001 respectively, n=8 in each group). In conclusion, long-term metabolic syndrome in FR significantly decreases bladder NGF and p75(NTR) expression. These alterations are associated with deterioration in bladder emptying function.