Untreated Obese Rats Research Articles

Capsinoids Increase Antioxidative Enzyme Activity and Prevent Obesity-Induced Cardiac Injury without Positively Modulating Body Fat Accumulation and Cardiac Oxidative Biomarkers.

Capsinoids are potential antioxidant agents capable of reducing oxidative damage and the resulting complications triggered by obesity. Thus, this study aimed to investigate the effects of capsinoids on adiposity and biomarkers of cardiac oxidative stress in obese rats induced by a high-fat diet. Male Wistar rats were exposed to a high-fat diet for 27 consecutive weeks. After the characterization of obesity (week 19), some of the obese animals began to receive capsinoids (10 mg/kg/day) by orogastric gavage. Adiposity and comorbidities were assessed. In the heart, remodeling, injury, and biomarkers of oxidative stress were determined. The treatment did not reduce obesity-induced adiposity but was efficient in reducing cholesterol levels. Capsinoid treatment did not cause a difference in heart and LV mass, despite having reduced troponin I concentrations. Furthermore, capsinoids did not reduce the increase in the advanced oxidation of protein products and carbonylated proteins caused by obesity in cardiac tissue. In addition, obese rats treated with capsinoids presented high levels of malondialdehyde and greater antioxidant enzyme activity compared to untreated obese rats. In conclusion, treatment with capsinoids increases antioxidative enzyme activity and prevents obesity-induced cardiac injury without positively modulating body fat accumulation and cardiac oxidative biomarkers.

Combination of Metformin and Epigallocatechin-3-Gallate Lowers Cortisol, 11β-Hydroxysteroid Dehydrogenase Type 1, and Blood Glucose Levels in Sprague Dawley Rats with Obesity and Diabetes.

The combined effects of metformin and epigallocatechin-3-gallate (EGCG) on cortisol, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), and blood glucose levels have not been investigated. This study evaluated the effectiveness of combining EGCG with metformin in regulating those levels in a rat model of diet-induced diabetes and obesity. Thirty diabetic and obese rats on a high-fat diet were treated daily for 28 days with EGCG (100 mg/kg of body weight/day), metformin (200 mg/kg of body weight/day), or both. Control groups comprised lean rats, untreated obese diabetic rats, and metformin-only-treated rats. Blood samples were collected to measure cortisol and fasting blood glucose (FBG) levels and liver tissue samples were examined for 11β-HSD1 levels. Rats receiving combination therapy had significantly reduced cortisol levels (from 36.70±15.13 to 31.25±7.10 ng/mL) compared with the untreated obese diabetic rats but not the rats receiving monotherapy. Rats receiving combination therapy and EGCG monotherapy had significantly lower 11β-HSD1 levels compared with the untreated obese diabetic rats (92.68±10.82 and 93.74±18.11 ng/L vs. 120.66±14.00 ng/L). Combination therapy and metformin monotherapy significantly reduced FBG levels (440.83±133.30 to 140.50±7.36 mg/dL and 480.67±86.32 to 214.17±102.78 mg/dL, respectively) by approximately 68.1% and 55.4% compared with rats receiving EGCG monotherapy and untreated obese diabetic rats. Combining EGCG with metformin exhibited synergistic effects compared with monotherapy for managing diabetes, leading to improved outcomes in reduction of baseline cortisol levels along with reduction in 11β-HSD1 and blood glucose levels.

Perindopril and losartan affect ACE-2 and IL- 6 expression in obese rat model.

Obesity has emerged as a worldwide health concern due to its increasing prevalence. Adipocytes have the ability to express angiotensin-converting enzyme 2 receptors (ACE2) and several adipocytokines. These expressions could lead to the activation of a cytokine storm, which in turn promotes the development of cardiovascular diseases. The aim of this study was to investigate the impact of perindopril and losartan exposure on the ACE2 and interleukin 6 (IL-6) levels in adipocyte cells. This study used an in vivo true experimental design utilizing a post-test-only control group. A total of 24 adult male albino rats were divided into four groups, one group served as the non-obese (negative control), while the other three groups were obese: (1) the positive control (untreated obese rats); (2) perindopril group (2 mg/kg BW/day orally for 4 weeks); and (3) losartan group (20 mg/kg BW/day for 4 weeks). Afterwards, the rats were euthanized, and the visceral fat tissue were obtained during dissection. The levels of ACE2 and IL-6 were measured using the enzyme-linked immunosorbent assay (ELISA). Losartan administration in obese rats resulted in a notable elevation in ACE2 levels compared to both the perindopril group (losartan vs perindopril, p=0.011) and the positive control (p=0.004). In addition, the treatment of perindopril and losartan in obese rats resulted in a significant reduction in IL-6 levels when compared to the positive control (perindopril vs positive control, p=0.020; losartan vs positive control, p=0.002, respectively). This study provides insight into the administration of perindopril and losartan, which could suppress the pro-inflammatory (IL-6) but increase the ACE2 levels in adipose tissue.

Empagliflozin improves diastolic function in obese ZSF1 rats by restoring the cardiac mitochondrial respiratory capacity

Abstract Background Clinical studies demonstrated beneficial effects of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) on the combined risk of cardiovascular death or heart failure hospitalization in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes leading to cardioprotection remain unclear. Purpose The present study aimed to elucidate the impact of Empagliflozin on myocardial function and metabolism in a rat model (ZSF1 rat) with established HFpEF and to analyze underlying mechanisms. Methods 24 week old, obese ZSF1 rats were randomized either receiving standard care (obese) or Empagliflozin (Empa, 30 mg/kg/d p.o.). ZSF1 lean rats (lean) served as healthy controls. All animals underwent a baseline, intermediate and final echocardiography. After 8 weeks of treatment, hemodynamics were measured invasively, blood samples were taken, cardiac mitochondrial function was assessed and left ventricular tissue was collected for molecular and histological analyses or for transmission electron microscopy (TEM). Results Compared to the obese control Empa treated obese rats demonstrated a significantly improved diastolic function already at 4 weeks of treatment (E/é: lean: 17.9 ± 0.8; obese: 23.7 ± 0.7, p<0.001 vs. lean; Empa: 21.0 ± 1.1, p<0.05 vs. lean; p<0.05 vs. obese), which reached the level of healthy controls after 8 weeks of treatment (E/é: lean: 17.5 ± 0.7; obese: 24.4 ± 1.1, p<0.001 vs. lean; Empa: 19.4 ± 0.8, p<0.001 vs. obese). This was accompanied by reduced hypertrophy, fibrosis, left ventricular stiffness and inflammation as well as by improved hemodynamics. Except for a slightly improved myocardial ketone body utilization in Empa treated rats, there was no shift in metabolic substrate preference between groups. Cardiac mitochondrial respiratory function observed in untreated obese rats was significantly impaired compared to healthy controls but restored by Empa treatment (Vmax of complex II: lean: 0.15 ± 0.007 nmol O2/s/mg, obese: 0.12 ± 0.004 nmol O2/s/mg, p<0.01 vs. lean; Empa: 0.17 ± 0.006 nmol O2/s/mg, p<0.05 vs. lean, p<0.001 vs. obese). Moreover, mitochondrial respiratory capacity correlated with diastolic function, suggesting a pivotal role of restored respiratory function for improved diastolic relaxation. TEM revealed reduced size of cardiac mitochondria in obese rats, which was significantly restored by Empa. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation and antioxidant metabolism. Conclusions The present study demonstrates for the first time beneficial effects of Empaglifozin on cardiac remodeling, diastolic function and hemodynamics in an obese rat model of HFpEF. These effects were accompanied by improved mitochondrial respiratory function, enhanced ketone body utilization and improved antioxidant capacity.

Leucine Supplementation Improves Diastolic Function in HFpEF by HDAC4 Inhibition.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with a high morbidity and mortality rate. Leucine supplementation has been demonstrated to attenuate cardiac dysfunction in animal models of cachexia and heart failure with reduced ejection fraction (HFrEF). So far, no data exist on leucine supplementation on cardiac function in HFpEF. Thus, the current study aimed to investigate the effect of leucine supplementation on myocardial function and key signaling pathways in an established HFpEF rat model. Female ZSF1 rats were randomized into three groups: Control (untreated lean rats), HFpEF (untreated obese rats), and HFpEF_Leu (obese rats receiving standard chow enriched with 3% leucine). Leucine supplementation started at 20 weeks of age after an established HFpEF was confirmed in obese rats. In all animals, cardiac function was assessed by echocardiography at baseline and throughout the experiment. At the age of 32 weeks, hemodynamics were measured invasively, and myocardial tissue was collected for assessment of mitochondrial function and for histological and molecular analyses. Leucine had already improved diastolic function after 4 weeks of treatment. This was accompanied by improved hemodynamics and reduced stiffness, as well as by reduced left ventricular fibrosis and hypertrophy. Cardiac mitochondrial respiratory function was improved by leucine without alteration of the cardiac mitochondrial content. Lastly, leucine supplementation suppressed the expression and nuclear localization of HDAC4 and was associated with Protein kinase A activation. Our data show that leucine supplementation improves diastolic function and decreases remodeling processes in a rat model of HFpEF. Beneficial effects were associated with HDAC4/TGF-β1/Collagenase downregulation and indicate a potential use in the treatment of HFpEF.

Anti-obesity effect of collagen peptides obtained from Diplulmaris antarctica, a jellyfish of the Antarctic region

To investigate the ability of collagen peptides derived from a jellyfish of the Antarctic region (Diplulmaris antarctica) to prevent the development of obesity in rats fed a high-calorie diet. Collagen peptides were produced by pepsin hydrolysis of jellyfish-derived collagen. The purity of collagen and collagen peptides was confirmed by SDS-polyacrylamide gel electrophoresis. Rats were fed a high-calorie diet for ten weeks and were simultaneously orally administered collagen peptides (1 g per 1 kg of body weight every other day) starting from the fourth week. Body mass index (BMI), body weight gain, selected nutritional parameters, the key parameters associated with insulin resistance, and the level of oxidative stress markers were assessed. Compared with untreated obese rats, rats treated with hydrolyzed jellyfish collagen peptides had a decreased body weight gain and body mass index. They also had a decreased level of fasting blood glucose, glycated hemoglobin, insulin, lipid peroxidation products (conjugated dienes, Schiff bases), and oxidatively modified proteins, as well as a restored activity of superoxide dismutase. Collagen peptides obtained from Diplulmaris antarctica can be used to prevent and treat obesity caused by a high-calorie diet and pathologies associated with increased oxidative stress. Given the obtained results and the abundance of Diplulmaris antarctica in the Antarctic region, this species can be considered a sustainable source of collagen and its derivatives.

Polygonatum sibiricum polysaccharides protect against obesity and non-alcoholic fatty liver disease in rats fed a high-fat diet

Polygonatum sibiricum is a traditional medicinal and dietary plant of the family Liliaceae. The main functional macromolecules of P. sibiricum are polysaccharides, which function in antioxidation and regulating immunity. Previous studies have shown that insulin resistance (IR), oxidative stress, and inflammation are important factors in the induction of lipid metabolic diseases such as obesity. Therefore, in this study, we established a high-fat diet-induced rat model of obesity and nonalcoholic fatty liver disease (NAFLD) to explore the potential protective effect of P. sibiricum polysaccharides (PSPs) and the mechanisms behind it. After 4 weeks of high-fat diet feeding to induce obesity, the rats were treated with different doses of PSP solution or distilled water for 6 weeks. Compared with untreated obese rats, PSP-treated obese rats showed a decrease in body weight, serum total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, hepatic aspartate aminotransferase and alanine aminotransferase activity, hepatic malondialdehyde content, and hepatic levels of the pro-inflammatory factors tumor necrosis factor-α, interleukin-1β, and interleukin-6, as well as increased serum high-density lipoprotein cholesterol levels and hepatic superoxide dismutase, catalase, and glutathione peroxidase activity. Pathological analysis and immunoblotting of the liver tissues indicated that mechanistically, PSPs reduced obesity and NAFLD in rats by upregulating insulin receptor expression, increasing adenosine monophosphate-activated protein kinase phosphorylation, and downregulating sterol regulatory element-binding protein 2 and low-density lipoprotein receptor expression, thus promoting lipid metabolism, decreasing body weight, and reducing inflammation and oxidative stress caused by lipid accumulation. Based on these results, PSPs may have the potential to reduce obesity and NAFLD associated with a high-fat diet.

Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility.

BackgroundAbout half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so‐called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed‐205) in HFpEF and to describe molecular changes elicited by MyoMed‐205.MethodsTwenty‐week‐old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed‐205 for 12 weeks; a comparison was made to age‐matched untreated ZSF1‐lean (healthy) and obese rats as controls. LV (left ventricle) function was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome‐wide analysis followed by WBs and RT‐PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1‐KO) SKM tissues were included to validate MuRF1‐specificity.ResultsBy week 32, untreated obese rats had normal LV ejection fraction but augmented E/e′ ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed‐205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed‐205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed‐205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed‐205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1‐KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1.ConclusionsMyoMed‐205 improved myocardial diastolic function and prevented SKM atrophy/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis.

Mentha Longifolia L. Improves Antioxidant Status, Glucose Tolerance, Insulin Resistance and Hepatic Glucose Production In Diet-Induced Obesity

Abstract Objectives Obesity is associated with several metabolic abnormalities including insulin resistance (IR), which is a key risk factor of type 2 diabetes mellitus (T2DM). Oxidative stress is linked to both obesity and IR development. Improving antioxidant status using medicinal plants or their bioactive components can be a safe and low-cost alternative approach to reduce obesity and IR thus T2DM development. This study aims to evaluate the antioxidant activities of Mentha longifolia L. (M. longifolia) leaf powder and oil extract on obesity-induced metabolic abnormalities. Methods High-fat-sucrose diet (HFS)-induced obese Wistar rats were orally given M. longifolia essential oil (50 mg/kg), leaf powder (120 mg/kg), or vehicle for 6 weeks. Bodyweight and calorie intake were recorded periodically, and glucose and pyruvate tolerance were evaluated. At the end of the study, plasma insulin and triglyceride levels were measured, and organs weight and the degree of adiposity were determined. Antioxidant status for the plasma was measured using plasma ferric ion reducing antioxidant power test (FRAP). Results M. longifolia leaf powder and oil extract improved glucose tolerance, and hepatic glucose production after being challenged with glucose or pyruvate compared to untreated obese rats. M. longifolia reduced IR (HOMA-IR: oil = 2.30 ± 0.279, powder = 2.13 ± 0.057, HFS = 2.54 ± 0.136). Antioxidant status was also improved in rats treated with M. longifolia (FRAP: oil = 300.5 ± 25.4, powder = 341.8 ± 47.2, HFS = 263.5 ± 13.0). These outcomes were not associated with changes in body weight, calorie intake, adiposity, or plasma triglycerides. Conclusions M. longifolia oil and powder improved the antioxidant status and ameliorated HFS diet-induced metabolic abnormalities, suggesting that this plant a promising natural agent for reducing the risk of T2DM. Further studies are needed to elucidate the mechanism of this action. Funding Sources Deanship of Scientific Research at Jordan University of Science and Technology.

Anti-inflammatory and protective effects of combined treatment with sitagliptin and melatonin in cardiac ischemia reperfusion injury in obese rats: Involvement of TLR-4/NF-κB pathway

Background: Obesity is associated with an augmented risk of myocardial ischemia/reperfusion (I/R) injury. Reduction of I/R injury by effective cardioprotective strategies needs to be investigated in obese subjects. This study aimed to evaluate the combined effects of sitagliptin and melatonin on inflammatory response and TLR4/IκBα/NF-κB signaling following cardiac I/R damage in obese rats. Methods: Sixty-six male Wistar rats (180–200 g) were fed a low fat diet (10% Kcal from lipids) or high fat (45% Kcal from lipids) diets for 12 weeks. High fat-fed (obese) rats experienced 30 min left anterior descending occlusion followed by 24 h reperfusion. Obese rats received sitagliptin (20 mg/kg/day) for 1 month before I/R surgery. Melatonin (10 mg/kg) was injected at early reperfusion. Myocardial infarct size (IS), cTn-I release, pro-inflammatory cytokines, myeloperoxidase (MPO), COX-2 and iNOS, and the protein expressions of TLR4, p-NF-κB/p65, and p-IκBα were evaluated. Results: Monotherapies with sitagliptin-preconditioning or melatonin-postconditioning had no cardioprotective effects in obese rats. However, combined therapy with sitagliptin and melatonin significantly reduced IS, and the release of cTn-I, in comparison to untreated obese rats ( p < .01) Moreover, this combination decreased the production of pro-inflammatory cytokines, MPO, COX-2 and iNOS, and the expression of TLR4 and p-NF-κB/p65, while reduced the expression of p-IκBα, in comparison with untreated or monotherapies-received obese rats ( p < .01 for all). Conclusion: Combination therapy with sitagliptin and melatonin was a good cardioprotective strategy to modulate the inflammatory responses and TLR4/NF-κB signaling pathway in obese patients with cardiac I/R injury.

Abstract 15172: Murf1 Inhibitor Embl205 is a New Approach for Treatment of Heart Failure With Preserved Ejection Fraction in an Animal Model

Background: The novel MuRF1 inhibitor EMBL205 attenuates effectively developing skeletal muscle atrophy and dysfunction in animals with heart failure with preserved ejection fraction (HFpEF, ZSF1 rat model). The impact of EMBL205 on myocardial function in the HFpEF setting is currently unknown and was evaluated in ZSF1 rats. Methods: 20 wks-old female obese ZSF1 rats received EMBL205 (12 wks, conc. of 0.1% in chow; HFpEF-EMBL205). Age-matched untreated lean (con) and obese (HFpEF) ZSF1 rats served as controls. At 32 wks of age left ventricular (LV)-, aortic valve (AV) function and LV end diastolic pressure (LVEDP) was determined by echocardiography and invasive hemodynamic measurements. LV expression of collagen 1A (Col1A) and 3A (Col3A) was assessed by qRT-PCR, MMP2 expression was obtained by zymography and perivascular fibrosis was quantified in histological sections. Results: Development of HFpEF in ZSF1 obese animals is associated with cardiac enlargement and hypertrophy, as evident by increased myocardial weight, an increase in end diastolic volume (EDV) and LV anterior and posterior wall diameters. Diastolic LV-function is disturbed with elevation of E/é, an increased LVEDP and a preserved LV ejection fraction. AV peak velocity and peak gradient are significantly increased and AV opening area (AVA) significantly decreased. Col1A and Col3A expression are increased in HFpEF animals. EMBL205 treatment results in a significant reduction of myocardial weight and a trend towards lower EDV compared to HFpEF group. EMBL205 attenuates the increase in E/é, LVEDP, AV peak gradient and the decrease of AVA. EMBL205 significantly reduces Col3A expression and a trend for Col1A expression is seen. Increased perivascular fibrosis and MMP2 expression in HFpEF is extenuated by EMBL205 treatment (table 1). Conclusions: Application of EMBL205 attenuated the development of pathological myocardial alterations associated with HFpEF in ZSF1rats due to antifibrotic effects.

Protective Potential and Antidiabetic Activity of Bilberry Leaves in Zucker Rats

Objective: The protective potential of Bilberry Leaves Extract (BLE) was studied in the experiment on male diabetic obese Zucker rats (ZDF) rats (Crl:ZUC-Lepr(fa)) with liver metabolism disorders and hyperglycemia. Methods: Animals were fed with or without BLE (2 g/kg b.w.) orally via a gastric tube for 28 days. At the end of the experiment, biochemical and morphological indices were studied. Results: Daily intake of BLE in obese ZDF rats produced a marked and sustained decrease in body weight without an increase in food intake in comparison with untreated obese rats. By the end of the study, fasting blood glucose for rats receiving BLE was significantly lower than in control group (P<0.05). The serum levels of aspartate aminotransferase and alkaline phosphatase, biomarkers of liver damage, were significantly (P<0.05) lower in BLE group compared to the obese control animals. There were also reductions (P<0.05) in total cholesterol and high-density lipoproteins levels associated with BLE treatments. BLE administration to obese rats significantly reduced serum urea levels compared to the untreated obese rats. The results also showed a decrease in liver/body weight ratio which is undoubtedly a positive effect together with a general reduction in body weight in BLE treated animals. Conclusion: These data suggest that BLE inhibited the development of hyperglycemia, improved lipid metabolism, and influenced positively on some integral indices and a histological picture in the target organs of obese ZDF rats.

Resveratrol protects against oxidative stress by activating the Keap-1/Nrf2 antioxidant defense system in obese-asthmatic rats.

The aim of the present study was to investigate the potential mechanism underlying the anti-obesity-asthmatic effects of resveratrol (RSV) in a rat model of obese-asthma. Rat models of obesity and asthma were established using a high-fat diet and the administration of ovalbumin, respectively. Rats were divided into 7 different groups: A normal control, a normal obese, a normal asthma, a normal obese + asthma, a RSV obese, a RSV asthma and a RSV obese + asthma group. Body weight, Lee index, body fat and lung histopathological changes were evaluated. Serum lipid levels were evaluated using calorimetric methods. Levels of reactive oxygen species (ROS) were examined using enzyme-linked immunosorbent assays. Cellular antioxidant enzyme activities were measured using commercial kits. Levels of kelch-like ECH associated protein 1 (Keap-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) was examined using western blot analysis. The results indicated that obese and asthma rat models were successfully established. It was also demonstrated that RSV decreased fasting blood glucose in obese, asthmatic and obese-asthmatic rats. RSV altered serum lipid levels; it significantly increased high density lipoprotein cholesterol levels and significantly decreased serum triglyceride, serum total cholesterol and very low density lipoprotein levels, compared with untreated obese, asthmatic and obese-asthmatic rats (P<0.05). ROS levels were significantly decreased in the RSV treatment group compared with obese, asthmatic and obese-asthmatic rats (P<0.05). RSV treatment significantly increased catalase, glutathione, glutathione peroxidase and total superoxide dismutase levels compared with untreated obese, asthmatic and obese-asthmatic rats (P<0.05). Furthermore, RSV treatment significantly downregulated Keap-1 and upregulated Nrf2 levels in the heart, lung and kidney tissues of rats compared with untreated controls. Therefore, the results demonstrate that RSV protects against oxidative stress by activating the Keap-1/Nrf2 antioxidant defense system in obese-asthmatic rat models.

Effect of a Homemade Fiber‐Rich Food and Polyherbal Formulation in High‐Fat Diet Induced Obese Rats

IntroductionThe treatment of obesity is difficult and challenging because of its obscure etiology. Consumption of a high‐fat diet is considered one of the major risk factors for the development of obesity. A direct link between high‐fiber diets and lower body weight has been shown in humans. Some medicinal herbs prove to have significant anti‐obesity and antioxidant effects.HypothesisWe hypothesize that the efficacy in consumption of a homemade formulated high‐fiber food is as good as commercially available polyherbal supplements in terms of weight reduction, economic and safety.MethodsA homemade fiber‐rich food was formulated with Kodomillet(Paspalum scrobiculatum), sprouted Bengal gram (Cicer airenitum) and Drumstick leaves (Moringa oleifera) in the ratio of 70:25:5 and a commercially available weight reducing polyherbal formulation was obtained from Zigma Herbal Remedies. Thirty 3‐month‐old male Sprague– Dawley rats, weighing between 200 and 250g, were randomly segregated into five groups of six rats each. The animal experiments were performed in accordance with the guidelines and approval of the Institutional Animal Ethics Committee. Four groups were fed with high‐fat diets consisting of 50% normal rat chow pellet, 24% corn oil, 20% full‐cream milk powder, and 6% sugar to induce obesity. The control rats were fed with normal rat chow for 4 weeks. These rats were used for subsequent 4 weeks of experimentation with homemade and commercially made polyherbal formulation. The treatment protocol included Group I as the normal control and received 10ml/Kg of normal saline. Group II served as high‐fat diet induced obese rats, and Group III served as the positive control and received Sibutramine (5mg/Kg) orally. Group IV, the obese rats received homemade food at a dose of 25mg/Kg twice a day daily. The Group V obese rats were fed with commercial polyherbal formulation at a dose of 25mg/Kg twice a day, daily. Plasma lipid profile, plasma leptin, insulin, glucose, liver function tests and histopathology were analyzed in biological samples after the experimentation period.ResultsThe rats exposed to high‐fat diet for 4 weeks had a significant increase in body weights, thus, confirming the obese status. The supplementation of obese rats with homemade food and commercial polyherbal formulation caused a remarkable reduction of body weights, and adipocytes loss as indicated by reduced leptin and insulin levels. Moreover, the total cholesterol and LDL levels were significantly reduced, and an increased HDL level (&gt;50%) observed in plasma when compared to the untreated obese control rats. The findings indicated that homemade food and polyherbal formulation play a role in the reversion of metabolic changes caused by high‐fat diet.ConclusionThe present investigation proved that the homemade food and commercial polyherbal formulation have the ability to lower the lipid levels and increase the weight‐reducing ability in obesity‐induced rats. Though the homemade fiber‐rich food was nearly two percent less effective when compared to the commercial polyherbal formulation, the homemade food is much safer and more economical when treating obesity.Support or Funding Informationnil

The effect of four-week levothyroxine treatment on hormonal regulation of adenylyl cyclase in the brain and peripheral tissues of obese rats

The decrease in the function of thyroid gland (TG), which is often observed in obesity and metabolic syndrome, results in the hypothyroid state and is one of the causes of metabolic and functional disorders. It is assumed that thyroid hormone treatment normalizing hormone levels in an organism is able to prevent these disorders. However, studies of the effect of this therapy on metabolic parameters in animals with experimental obesity are very scarce, and data concerning its influence on the activity of the adenylyl cyclase signaling system (ACSS) are absent. At the same time, it is known that disturbances in the hormonal regulation of ACSS play a key role in etiology and pathogenesis of diseases associated with metabolic disorders. This work was aimed at studying the effect of long-term levothyroxine treatment of obese male rats on their carbohydrate and lipid metabolism, thyroid status, and the activity of ACSS and its hormonal regulation in the brain, myocardium, epididymal fat, and TG. The rats with obesity caused by a three-month high-fat diet received levothyroxine for four weeks (orally, with a daily dose of 20 μg/kg) (group OB + LT), whereas the control animals and untreated obese rats received placebo instead of the hormone. As a result of the treatment, the levels of thyroid hormones increased, the body and adipose tissue weight decreased, the levels of triglycerides, total and atherogenic cholesterol decreased, and glucose utilization increased. In addition, the ACSS activity impaired in obesity was restored in the brain, myocardium, and epididymal fat tissue. In the brain, the levothyroxine treatment restored the stimulatory effects of serotonin and dopamine, as well as the inhibitory effects of the agonists of the subtype 1B 5-hydroxytryptamine receptor and type-2 dopamine receptor on the adenylyl cyclase (AC) activity. In the myocardium, the stimulatory effects of β1/β2-agonists and relaxin reduced in obesity were also restored. It should be noted, however, that the effects of β3-agonists augmented in obesity did not change in group OB + LT, resulting in the enhanced activating influence of β-agonists on AC and creating certain risks of the development of cardiovascular diseases. The increase in the lipolytic effect of β-agonists and the weakening of the antilipolytic effect of N6-cyclopentyladenosine, an agonist of type 1 adenosine receptor, was found in the epididymal fat, indicating the increased lipolysis in adipose tissue. The sensitivity of AC to the thyroid-stimulating hormone in TG decreased in group OB + LT with an excess of thyroid hormones. Thus, the treatment with levothyroxine not only improves the energy metabolism and prevents the deficiency of thyroid hormones in experimental obesity but also restores the hormonal regulation of ACSS, which can be one of the mechanisms of action of thyroid hormones on the brain and peripheral tissue functions in obesity and other metabolic disorders associated with the hypothyroid state.

Renal protective effects of induction of haem oxygenase-1 combined with increased adiponectin on the glomerular vascular endothelial growth factor-nitric oxide axis in obese rats.

What is the central question of this study? This study aimed to investigate whether induction of haem oxygenase-1 (HO-1) can protect the kidneys of obese rats by regulating the glomerular vascular endothelial growth factor-nitric oxide (VEGF-NO) axis by increasing the adiponectin concentrations. What is the main finding and its importance? Induction of HO-1 reduces the degree of microalbuminuria and has renal protective effects by improving endothelial function and regulating the uncoupled glomerular VEGF-NO axis in diet-induced obese rats. The mechanism may be related to increased activation of the HO-1-adiponectin axis. The glomerular vascular endothelial growth factor-nitric oxide (VEGF-NO) axis plays a critical role in maintenance of normal kidney function in obesity. Induction of haem oxygenase-1 (HO-1) may result in a parallel increase in adiponectin secretion. The aim of this study was to investigate whether induction of HO-1 could protect the kidneys of obese rats by regulating the glomerular VEGF-NO axis by increasing adiponectin levels. Rats received high-fat diets and were injected with either cobalt protoporphyrin to induce HO-1 or stannous protoporphyrin to inhibit HO-1. Blood and urine samples were collected. Endothelial function was determined by measuring the endothelium-dependent vasodilatation of the aorta. Renal tissues were collected for CD34 immunohistochemistry. The glomerular VEGF-NO axis and the AMP kinase-phosphoinositide 3-kinase (PI3K)/Akt-endothelial nitric oxide synthase pathway were measured. Induction of HO-1 by cobalt protoporphyrin decreased microalbuminuria, plasma free fatty acids, serum high-sensitivity C-reactive protein and malondialdehyde levels and increased serum adiponectin levels compared with the untreated obese rats. Severe impairment of endothelium-dependent vasodilatation was observed in the obese rats, which was improved to some extent by HO-1 induction. Induction of HO-1 reduced glomerular CD34 expression and production of reactive oxygen species in obese rats. Obese rats showed increased glomerular VEGF expression and reduced NO levels. This uncoupling of the glomerular VEGF-NO axis was improved to some extent by induction of HO-1, with enhancement of p-AMP kinase, p-Akt and phospho-endothelial nitric oxide synthase in obese rats. These results indicate that induction of HO-1 with cobalt protoporphyrin reduces the degree of microalbuminuria and has renal protective effects by improving endothelial dysfunction and regulating the glomerular VEGF-NO axis in diet-induced obese rats by increasing adiponectin levels.

Obestatin and l-carnitine as a defensive strategy against fertility disorders induced by obesity in male rats

Aim This study was designed to investigate the usage of obestatin (OB) and l-carnitine (LC) as a defensive strategy against fertility disorders induced by obesity in male rats. Materials and methods The study was carried out on 50 male Wistar rats, which were divided into five groups as follows: the control group, untreated obese rats, obese rats treated with OB, obese rats treated with LC, and obese rats treated with both OB and LC. Results The induction of obesity resulted in significant increase in body weight, plasma level of triglyceride, total cholesterol, low-density lipoprotein-cholesterol, and thiobarbituric acid reactive substance as compared with the control group. In addition, it produced significant lower activities of superoxide dismutase, catalase, and glutathione peroxidase antioxidant enzymes (GHP-Px) in testicular tissue. There was reduced plasma testosterone, follicle stimulating hormone, luteinizing hormone, and low-density lipoprotein-cholesterol and decreased sperm count and motility. OB significantly lowers body weight, plasma levels triglyceride, total cholesterol, low--density lipoprotein-cholesterol, and testicular thiobarbituric acid reactive substance level. These changes were coupled with significant increase in antioxidant enzymes activities in testicular tissue with significant increase in testosterone plasma level and sperm count and motility. This was accompanied by insignificant increase in plasma follicle stimulating hormone and luteinizing hormone levels. LC produced similar but better changes in all parameters except body weight. Moreover, the concomitant administration of both OB and LC to obese rats resulted in more improvement in all parameters than that were noticed in group III or IV. Conclusion The results of the study verified the possible combined use of OB and LC as a defensive strategy against fertility disorders induced by obesity. OB has the upper hand as anorexigenic agent, whereas LC is superior against obesity as a case of secondary hypogonadism.

Novel effects of the cannabinoid inverse agonist AM 251 on parameters related to metabolic syndrome in obese Zucker rats

Background and ObjectiveRecent research suggests that cannabinoid receptor CB1 antagonists can affect appetite and body weight gain, although their influence on other parameters related to metabolic syndrome is not well documented. The present study was designed to assess the effects of chronic treatment with the CB1 receptor inverse agonist AM 251 (3mg/kg for 3weeks) in obese and lean Zucker rats on parameters related to metabolic syndrome. Materials and MethodsFour groups of rats were used: lean Zucker rats, untreated obese Zucker rats, AM 251-treated obese Zucker rats and a pair-fed obese Zucker rat experimental group which received the same amount of food as that consumed by the animals treated with AM251. Food intake, body weight gain, energy expenditure, plasma biochemical parameters, leptin, insulin and hepatic status markers were analysed. ResultsDaily injection of AM 251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM 251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. The results also showed a decrease in liver/weight body ratio and total fat content in the liver. The main effects of AM251 (3mg/kg) found in this study were not observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with AM 251. The results obtained in obese rats can be interpreted as a decrease in leptin and insulin resistance, thereby improving glucose and lipid metabolism, alleviating the steatosis present in the metabolic syndrome and thus favourably modifying plasma levels of hepatic biomarkers. ConclusionOur results indicate that the cannabinoid CB1 inverse agonist AM 251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.

113th Annual Meeting of the American Associaton of Colleges of Pharmacy, Kissimmee, FL, July 14-18, 2012

113th Annual Meeting of the American Associaton of Colleges of Pharmacy, Kissimmee, FL, July 14-18, 2012

MR Molecular Imaging of Aortic Angiogenesis

The objectives of this study were to use magnetic resonance (MR) molecular imaging to 1) characterize the aortic neovascular development in a rat model of atherosclerosis and 2) monitor the effects of an appetite suppressant on vascular angiogenesis progression. The James C. Russell:LA corpulent rat strain (JCR:LA-cp) is a model of metabolic syndrome characterized by obesity, insulin resistance, hyperlipidemia, and vasculopathy, although plaque neovascularity has not been reported in this strain. MR molecular imaging with alpha(nu)beta(3)-targeted nanoparticles can serially map angiogenesis in the aortic wall and monitor the progression of atherosclerosis. Six-week old JCR:LA-cp (+/?; lean, n = 5) and JCR:LA-cp (cp/cp; obese, n = 5) rats received standard chow, and 6 obese rats were fed the appetite suppressant benfluorex over 16 weeks. Body weight and food consumption were recorded at baseline and weeks 4, 8, 12, and 16. MR molecular imaging with alpha(nu)beta(3)-targeted paramagnetic nanoparticles was performed at weeks 0, 8, and 16. Fasted plasma triglyceride, cholesterol, and glucose were measured immediately before MR scans. Plasma insulin and leptin levels were assayed at weeks 8 and 16. Benfluorex reduced food consumption (p < 0.05) to the same rate as lean animals, but had no effect on serum cholesterol or triglyceride levels. MR (3-T) aortic signal enhancement with alpha(nu)beta(3)-targeted nanoparticles was initially equivalent between groups, but increased (p < 0.05) in the untreated obese animals over 16 weeks. No signal change (p > 0.05) was observed in the benfluorex-treated or lean rat groups. MR differences paralleled adventitial microvessel counts, which increased (p < 0.05) among the obese rats and were equivalently low in the lean and benfluorex-treated animals (p > 0.05). Body weight, insulin, and leptin were decreased (p < 0.05) from the untreated obese animals by benfluorex, but not to the lean control levels (p < 0.05). Neovascular expansion is a prominent feature of the JCR:LA-cp model. MR imaging with alpha(nu)beta(3)-targeted nanoparticles provided a noninvasive assessment of angiogenesis in untreated obese rats, which was suppressed by benfluorex.