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in Obese Zucker Rats1
Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain and * Research Department of Madaus S.A., Barcelona, Spain
2To whom correspondence should be addressed. E-mail: mgalist{at}ugr.es.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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(TNF-) were determined, and studies on vascular function were performed using aortic rings. Rats fed the P. ovata husk-supplemented diet had a significantly reduced body weight gain compared with those fed the standard diet. Decreased endothelium-dependent relaxation in response to acetylcholine (ACh) by aortic rings from obese Zucker rats was improved in those fed the fiber-supplemented diet. The greater SBP, higher plasma concentrations of triglycerides, total cholesterol, FFA, glucose, insulin, and TNF-, and the hypoadinectinemia that occurred in obese Zucker rats that consumed the control diet were significantly improved in those fed the fiber-supplemented diet. We conclude that intake of a P. ovata husk-supplemented diet prevents endothelial dysfunction, hypertension, and obesity development, and ameliorates dyslipidemia and abnormal plasma concentrations of adiponectin and TNF- in obese Zucker rats.
KEY WORDS: • metabolic syndrome • endothelial dysfunction • hypertension • obese Zucker rats • Plantago ovata husks
The metabolic syndrome refers to a condition in which several specific abnormalities including abdominal obesity, dyslipidemia, and arterial hypertension are all present, with insulin resistance as the primary defect (1). This syndrome is directly associated with an increased risk of developing cardiovascular diseases (2,3), the major causes of premature mortality in type 2 diabetes patients.
Obesity/insulin resistance is associated with endothelial dysfunction (4), which plays a pivotal role in cardiovascular risk. The mechanisms that link obesity, insulin resistance, and endothelial dysfunction are numerous and complex (4). Obesity, usually involving increased visceral fat, leads to an imbalanced production of metabolic products, hormones, and adipocytokines such as FFAs, tumor necrosis factor- (TNF-),3 or adiponectin, which favors decreased insulin sensitivity in skeletal muscle and liver, and impairs endothelial function through direct and/or indirect mechanisms.
The obese Zucker rat is a widely used animal model of insulin resistance with features resembling human metabolic syndrome because resistance to the metabolic actions of insulin, dyslipidemia, mild glucose intolerance, hyperinsulinemia are all present (2,5); in some colonies, hypertension develops by 4–5 mo of age (6). In contrast, their lean littermates are insulin sensitive, normoinsulinemic, normotensive, and have a normal lipid profile and glucose tolerance.
Some recent clinical studies showed that both nonpharmacologic and pharmacologic strategies targeting obesity and/or insulin resistance ameliorate endothelial dysfunction and reduce cardiovascular risk in individuals with diabetes. Among the nonpharmacologic approaches, there is a growing body of literature supporting the beneficial effects of fiber-rich foods for optimal health and disease prevention. A high intake of fiber-rich carbohydrates also contributes to weight management (7,8) and is beneficial for reducing the risk of cardiovascular disease (9,10) and diabetes (7,11,12). Few epidemiologic data exist on the relation between different types of dietary fiber intake and the incidence of type 2 diabetes. Psyllium is a mucilaginous material prepared from the seed husk of plants of the Plantago genus and an excellent source of mainly soluble fiber. Its addition to a standard diet for diabetes is safe and well tolerated; it improves glycemic and lipid control in individuals with type 2 diabetes and hypercholesterolemia (13). Psyllium has hypolipidemic effects in both human and animal feeding studies (14,15) and attenuates hypertension in experimental models (16).
Although there is an increasing body of literature supporting the beneficial effects of dietary fiber such as psyllium or other preparations obtained from the husks or seeds of P. ovata, to our knowledge, there are no studies stating the effect of this dietary fiber on endothelial dysfunction and on hypertension associated with type 2 diabetes in experimental models, or analyzing its effects on metabolic products involved in insulin resistance other than lipids. The aim of the present study was to evaluate whether long-term intake of a fiber-supplemented diet (3.5% P. ovata husks) has preventive effects in the development of abnormalities developed in the experimental model of obese Zucker rats.
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MATERIALS AND METHODS |
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Reagents and diets. All chemicals were obtained from Sigma Chemicals. P. ovata husks were provided by Madaus S.A. as plantaben. The fiber-supplemented diet was prepared by adding 5 g of plantaben to 95 g of pulverized standard diet for rats (Table 1).
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Obese and lean rats were randomly assigned to 2 groups; the control group was fed standard diet and the other group consumed the fiber-supplemented diet. The lean and obese rats groups fed the standard diet are designated as LC and OC, respectively, whereas those consuming the fiber-supplemented diet are designated as LP and OP. During the experimental period of 25 wk, rats had free access to tap water and diet, and food intake was measured daily.
Blood pressure measurements. Systolic blood pressure (SBP) was determined once a month, in the morning, in conscious, prewarmed, restrained rats by tail-cuff plethysmography (digital pressure meter, LE 5000, Letica S.A.). At least 7 determinations were made in every session and the mean of the lowest 3 values within 5 mm Hg was taken as the SBP value.
Samples collection and storage. At the end of the experimental period, rats were killed and blood was obtained to analyze biochemical variables. Thoracic aorta, kidneys, liver, and heart were excised, cleaned, and weighed. The relative liver, heart, and kidney weights were calculated by dividing the liver, heart, and kidney weight by the body weight. Plasma was obtained by blood centrifugation at 2000 x g for 15 min, divided into aliquots, and frozen.
Plasma analytical procedures.
Plasma glucose, triglycerides, and total cholesterol concentrations were measured by colorimetric methods using Spinreact kits (Spinreact). Plasma FFA concentration was determined using a Wako NEFA C test kit (Wako Chemicals). Plasma insulin concentration was quantified using a rat insulin enzyme immunoassay kit (Amersham Biosciences). TNF- concentration in plasma was determined using a rat TNF- ELISA kit (Biosource International). Plasma adiponectin concentration was determined using a mouse/rat adiponectin ELISA kit (B-Bridge International). Ghrelin concentration in plasma was measured using a rat ghrelin enzyme immunoassay kit (Phoenix Pharmaceuticals).
In vitro endothelial function. Ring segments (3 mm) of the descending thoracic aorta were dissected and mounted in individual organ chambers filled with Krebs buffer of the following composition (mmol/L): NaCl, 118; KCl, 4.75; NaHCO3, 25; MgSO4, 1.2; CaCl2, 2; KH2PO4, 1.2; and glucose, 11. The solution was gassed continuously with a 95% O2:5% CO2 mixture, and maintained at 37°C. Rings were stretched to 2 g of resting tension by means of 2 L-shaped stainless steel wires inserted into the lumen and attached to the chamber and to an isometric force-displacement transducer (Letigraph, model 2000, Letica S.A.), as previously described (17). After equilibration, concentration-relaxation response curves to acetylcholine (ACh) (10–9–10–5 mol/L) were performed in intact rings precontracted by 10–6 mol/L noradrenaline. The relaxant responses to sodium nitroprusside (SNP) (10–10–10–6 mol/L) were studied in the dark in endothelium-denuded vessels precontracted by 10–6 mol/L noradrenaline. Relaxant responses to ACh and SNP were expressed as a percentage of precontraction induced by noradrenaline.
Statistical analysis. Results are expressed as means ± SEM. Data were analyzed by 2-way ANOVA with Bonferroni’s post test using GraphPad Prism version 4.00 for Windows (GraphPad Software). Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Systolic blood pressure. SBPs increased slowly in obese Zucker rats as they aged and were greater than in the lean rats after 4 mo of treatment (P < 0.0001) (Fig. 2). Maximal SBPs were reached at the end of the experimental period. The increase in SBP in OP rats was slightly less than that in OC rats (P = 0.0152) (Fig. 2).
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Plasma biochemistry.
The elevated concentrations of triglycerides, FFA, and total cholesterol in plasma of OC rats compared with LC rats (P < 0.001) were reduced in OP rats (P < 0.0386) (Table 3). OC rats had a slight increase (P = 0.034) in plasma glucose concentration compared with LC rats. Intake of the fiber-supplemented diet normalized plasma glucose concentration in OP rats (Table 3). Elevated insulin plasma concentrations in OC rats were also reduced in OP rats (P = 0.019) (Table 3). Adiponectin plasma concentration, which was reduced in OC compared with LC rats (P < 0.05), was increased in OP rats (P = 0.0021) (Fig. 4). TNF- circulating concentrations, which were greatly increased in OC rats (P = 0.0226), were diminished in OP rats (P = 0.0250) (Fig. 4). Although the plasma concentration of ghrelin did not differ between the LC and OC groups, this variable was lower in OP rats than in OC rats (P = 0.0418) (Fig. 4).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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circulating concentration.
Obesity in Zucker rats and type 2 diabetes in humans are both characterized by TNF- overproduction in adipose tissues (18–20) and by decreased plasma concentration of adiponectin (19–21), which contribute to insulin resistance. Our results reveal reduced circulating concentrations of TNF- and increases in plasma adiponectin concentration in OP rats. Although the mechanisms by which P. ovata husks produce such effects are still unknown, they could be related to failure to gain weight as described in humans (22,23). In fact, a decreased weight gain was observed in both LP and OP rats, suggesting that this effect can be attributed not only to lower food intake by OP rats, but also to the lower energy intake of the P. ovata husk-supplemented diet due in part to dilution of nutrients by fiber incorporation. The properties of P. ovata husks likely contributed to the decrease in weight gain. In humans, psyllium delays gastric emptying, likely by increasing meal viscosity, which promotes a decrease in fat and sugar absorption. It also reduces the acceleration of colon transit, possibly by delaying the production of gaseous fermentation products (24).
Effects other than body weight reduction must be involved in those beneficial actions of P. ovata husks in Zucker obese rats because the lean rats had similarly decreased weight gain without changes in cardiovascular function or biochemical markers involved in insulin resistance. Ghrelin is a stomach-derived peptide that has proved to be an important regulator of energy homeostasis. At the age of 6 mo, lean and obese Zucker rats [(25) and present results] did not differ in plasma ghrelin concentration. Fiber-supplemented diet intake reduced this biochemical marker in OP rats, an effect that parallels the lower food intake in this group. In addition to this orexigenic effect, ghrelin reduces adiposity and adiponectin expression in adipose tissue and increases plasma insulin concentration (26,27). In this way, a reduction in ghrelin concentration in OP rats may account for reduced hyperinsulinemia and normalization of the plasma adiponectin concentration.
The lack of weight gain induced by P. ovata husks was accompanied by reduced liver hepatomegaly in OP rats. A reduction in liver weight has been associated with a decrease in the hepatic accumulation of triglycerides (28,29). Furthermore, the reduced concentrations of triglycerides and cholesterol in OP rats are in agreement with other studies in humans and animals (14,15). Although mechanisms are still not fully explained, the hypotriglyceridemic effects of P. ovata husks are consistent with a possible delay in the absorption of triglycerides and sugars from the small intestine (30). The psyllium hypocholesterolemic mechanisms were related previously to decreased cholesterol absorption or inhibition of the enterohepatic circulation of bile acids, due to the physicochemical properties of psyllium and to the increase it produces in meal viscosity (31).
Endothelial dysfunction and hypertension are closely related to obesity and/or insulin resistance (4). The obese Zucker rat model has been used extensively to characterize vascular dysfunction in type 2 diabetes. Although many studies reported that the endothelium-dependent relaxation in response to ACh is paradoxically preserved or even enhanced in obese Zucker rats relative to their lean littermates (32,33), impaired ACh-induced vasodilation was also described (34,35). Such variations likely arose in part because of differences in the arterial preparation used and the age of the rats. In the present study, the aortic rings from OC rats had a reduced endothelium-dependent vasodilator response induced by ACh compared with their lean littermates. Endothelial dysfunction was unrelated to changes in the guanylate cyclase-cGMP pathway because responses to the NO donor, SNP, were unchanged. Endothelium-dependent vasorelaxation in response to ACh was enhanced in OP rats. The mechanism of this action is unknown at present, but we speculate that it may involve the ability of P. ovata husk-supplemented diet to improve many of the altered concentrations of metabolic products that characterize obese Zucker rats because endothelial dysfunction has been related to high concentrations of cholesterol, triglycerides (36), FFA (37), and TNF- (38,39) and a low plasma concentration of adiponectin (40,41).
The lowering effect of psyllium supplementation on SBP was reported in stroke-prone spontaneously hypertensive rats (16,42). Our results show, for the first time, a slight but significant reduction in SBPs in OP rats. The increased endothelium-dependent vasodilation in response to ACh after long-term intake of such a diet could contribute to this effect. The hypotensive effect of psyllium in stroke-prone spontaneously hypertensive rats was attributed, at least in part, to its ability to inhibit intestinal absorption of Na+ (16), but this hypothesis was not explored in our study.
In conclusion, the present study show for the first time that prolonged intake of a 3.5% P. ovata husk-supplemented diet prevents endothelial dysfunction and retards obesity and the development of hypertension in obese Zucker rats, effects that were accompanied by an increase in plasma adiponectin, reductions in TNF- and FFA circulating concentrations, and amelioration of the dyslipidemia and hyperinsulinemia associated with this model. Our findings reinforce current dietary advice recommending the consumption of diets with a high fiber content to prevent type 2 diabetes (43), and confirm the beneficial effects of soluble fiber supplements such as P. ovata husks to avoid the progress of this pathology.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ACh, acetylcholine; LC, lean control rats; LP, lean rats fed the 3.5% P. ovata husk-supplemented diet; OC, obese control rats; OP, obese rats fed the 3.5% P. ovata husk-supplemented diet; SBP, systolic blood pressure; SNP, sodium nitroprussiate; TNF-, tumor necrosis factor .
Manuscript received 9 May 2005. Initial review completed 2 June 2005. Revision accepted 19 July 2005.
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