Obese Male Rats Research Articles

Combined gastrin releasing peptide-29 and glucagon like peptide-1 reduce body weight more than each individual peptide in diet-induced obese male rats

To test the hypothesis that gastrin releasing peptide-29 (GRP-29) combined with glucagon like peptide-1 (7–36) (GLP-1 (7–36)) reduce body weight (BW) more than each of the peptides given individually, we infused the two peptides (0.5nmol/kg each) in the aorta of free feeding, diet-induced obese (DIO) male Sprague Dawley rats once daily for 25days and measured BW. We found that GRP-29 and GLP-1 reduce BW, GRP-29 reduced it more than GLP-1 and GRP-29+GLP-1 reduce BW more than each peptide given alone. This reduction was accompanied by decrease 24-hour food intake (normal rat chow), meal size (MS), duration of first meal and number of meals, and increase latency to the first meal, intermeal interval (IMI) and satiety ratio (IMI/MS, amount of food consumed per a unit of time). Furthermore, the peptides and their combination decreased 24-hour glucose levels. In conclusion, GRP-29+GLP-1 reduce BW more than each of the peptides given individually.

Abstract P353: Attenuation of Cardiac Fibrosis, Hypertrophy and Myopathy by AT2R Agonist NP-6A4

Adverse cardiac remodeling (hypertrophy, fibrosis and myopathy) underlies cardiac dysfunction and heart failure. Male Zucker obese (ZO:fa/fa) rat that suffers from cardiac dysfunction, adverse remodeling, and heart failure with preserved ejection fraction is a useful model to study the effects of cardioprotective drugs. We reported that NP-6A4 (Novopyxis Inc. Cambridge, MA), a peptide agonist of the Angiotensin II Type 2 Receptor (AT2R), protected mouse cardiomyoblast HL-1 cells and human coronary artery vascular smooth muscle cells (hCAVSMCs) from acute nutrient serum deficiency stress better than β-AR-Blockers, ARBs, and AT2R agonist CGP42112A. This effect was inhibited by AT2R-specific antagonist PD123319, confirming that NP-6A4 acts through AT2R. AT2R is a cardiac and vascular reparative molecule that protects the heart and vasculature from structural damage and fibrosis. No current drugs increase AT2R expression. We report that NP-6A4 treatment (1μM) increased AT2R mRNA (up to 4 fold; p≤0.05) in hCAVSMCs and human coronary artery endothelial cells (up to 8 fold; p≤0.05). This effect was inhibited by PD123319 (10 μM). Treatment of 11-week old male ZO rats with heart disease with NP-6A4 (1.8mg/kg/day in saline, delivered once daily subcutaneously; N=7) increased cardiac AT2R expression and mitigated cardiac dysfunction and adverse remodeling. Quantitative RT-PCR and immunohistochemistry analysis showed that 2 weeks of NP-6A4 treatment increased cardiac AT2R mRNA (up to 9 fold) and protein (1.5-3 fold) compared to controls (N=6) receiving saline (p<0.01). NP-6A4 treatment improved cardiac parameters; endocardial circumferential strain (p≤0.05), myocardial performance index (MPI) (p≤0.005), and E/E’ ratio (p≤0.002). NP-6A4 treatment also increased cardiac capillary density (118% compared to saline treatedl; p≤0.002), and reduced interstitial fibrosis (77% compared to saline treated; p≤0.039.) At 19-weeks (after 8 weeks of treatment), cardiac tissues from 5 out of 6 control rats exhibited regions of myopathy. Only 2 out 7 NP-6A4 treated rats exhibited similar levels of myopathy in the heart. We propose that NP-6A4 attenuates adverse remodeling and improves cardiac function by increasing AT2R expression in cardiac cells.

Regulation of hepatic Na+/K+-ATPase in obese female and male rats: involvement of ERK1/2, AMPK, and Rho/ROCK.

In this study, we assessed whether the disturbed regulation of sodium/potassium-adenosine-triphosphatase (Na+/K+-ATPase) occurs as a consequence of obesity-induced IR in sex-specific manner. We also assessed whether alterations of IRS/PI3K/Akt, ERK1/2, AMPKα, and RhoA/ROCK signaling cascades have an important role in this pathology. Female and male Wistar rats (150-200g, 8weeks old) were fed a standard laboratory diet or a high-fat (HF) diet (42% fat) for 10weeks. The activity of hepatic Na+/K+-ATPase and Rho, and the association of IRS-1/p85 were assessed in liver. Furthermore, the protein level of α1 Na+/K+-ATPase in plasma membrane fractions, and protein levels of IRS-1, PI3K-p85, -p110, RhoA, ROCK1, ROCK2, ERK1/2, AMPKα, ERα, and ERβ in liver lysates were assessed. The expression of hepatic α1 Na+/K+-ATPase mRNA was also analyzed by qRT-PCR. The results show that HF-fed female rats exhibited an increase in hepatic ERK1/2 (p<0.05) and AMPKα (p<0.05) phosphorylation levels, unchanged level of Na+/K+-ATPase α1 mRNA, decreased level of Na+/K+-ATPase activity (p<0.05), and decreased α1 Na+/K+-ATPase protein expression (p<0.01). In liver of HF-fed male rats, results show decreased levels of Na+/K+-ATPase activity (p<0.01), both protein and mRNA of α1 subunit (p<0.05), but significant increase in Rho activity (p<0.05). Our results indicate significant sex differences in α1 Na+/K+-ATPase mRNA expression and activation of ERK1/2, AMPKα, and Rho in the liver. Exploring the sex-specific factors and pathways that promote obesity-related diseases may lead to a better understanding of pathogenesis and discovering new therapeutic targets.

Melioration of Fertility in High Fat Diet Induced Obese Male Wistar Rats using Polyherbal Formulation

Background: increased incidence of infertility due to various other complications is not properly diagnosed. A safe and effective medication to treat such complications is much needed. Objectives: To develop a Polyhedral Formulation (PHF) to treat obesity induced infertility in male wistar albino rats and to meliorate hyperlipidemia induced by High Fat Diet (HFD). Methods: Extracts of W. Somnifera roots, A. Racemosus roots and A. Paniculata leaves were used for PHF. For the experiment 24 male wistar albino rats of 4 weeks age were taken and divided into 4 groups. Three of the groups were fed with HFD for 4 weeks. For the next 2 weeks two of the groups were treated with 200 and 400mg/kg PHF respectively. Parameters like complete lipid profile, body weights, Body Mass Index (BMI), spermiogram, Lee index, Serum testosterone levels, energy consumption and litter size and antioxidant activity were estimated. Results: On 4th week, a significant (P&lt; 0.0001) increase in the body weight was observed in the HFD group compared to the control group. PHF treated groups showed a significant (P &lt; 0.05*, P&lt; 0.01**, P&lt; 0.001***) difference in all the parameters when compared to HFD group. Conclusion: From the observations of the study performed, it could be predicted that PHF exerted a significant anti-obese activity and an improved fertility rates in obese rats.

Cooking methods affect phytochemical composition and anti-obesity potential of soybean (Glycine max) seeds in Wistar rats.

This work aimed at investigating the effects of three domestic cooking methods (roasting, sprouting and boiling) on phytochemical contents (phenolic content, flavonoid, fibre), and anti-obesity (weight loss, hypoglycemic effect, serum lipids) potential of soybean seeds in obese male rats. Ten different forms were implemented, combining hulled/unhulled and raw/cooked soybean seeds using a basal and a hypercaloric diet as controls. Unhulled Roasted Soybean (URS) exhibited the highest phenolic content and a greater antioxidant activity by the FRAP assay than BHT at certain concentrations. Hulled boiled Soybean (HBS) showed the highest flavonoid content while Hulled Germinated Soybean (HGS) presented the lowest fibre content (P < 0.05). Unhulled Boiled Soybean (UBS) induced the best reduction in food intake while Unhulled Soybean Extract (USE) exhibited the greatest slimming effect. HBS exhibited the best cholesterol lowering ability; URS and Unhulled germinated Soybean (UGS) respectively induced the highest increase in HDL cholesterol levels and reduction in triglyceride levels. UBS demonstrated the highest ability to lower LDL cholesterol. UGS exhibited the highest ability to lower the postprandial blood glucose. Culinary treatments affect phytochemical content and anti-obesity potential of soybean seeds.

Anti-obesity and Anti-hepatosteatosis Effects of Dietary Zingiber officinale Extract in Male Obese Rats

Anti-obesity and Anti-hepatosteatosis Effects of Dietary Zingiber officinale Extract in Male Obese Rats

Pre-pubertal diet restriction reduces reactive oxygen species and restores fertility in male WNIN/Obese rat.

Obesity is a multifactorial disorder associated with increased body adiposity, chronic oxidative stress which contributes to impaired fertility in males. Diet restriction and anti-oxidant supplementations are known to protect obese subjects from oxidative stress and improves fertility. However, the role of oxidative stress and the age of intervention in restoring male fertility are poorly understood. This study was aimed to assess the effect of diet restriction on fertility with respect to the age of intervention, body composition and oxidative stress using WNIN/Ob obese mutant rat strain. Unlike lean and carrier phenotypes, obese rats are hyperphagic, hyperlipaemic and infertile. Male obese rats aged for 35, 60 and 90days were fed either ad libitum or diet restricted for 6weeks. Upon diet restriction mean body weight, total body fat percentage, circulatory lipids and oxidative stress markers were significantly reduced and it follows the order as 35<60<90days. Diet-restricted males of the three age groups were allowed to mate with female carrier rats, and fertility was restored only in 35-day group. Diet restriction in male obese WNIN/Ob rats lowered the rate of body weight gain, with reduced oxidative stress overall and fertility restoration in groups intervened at pre-pubertal stages.

Effects of Myricetin-Containing Ethanol Solution on High-Fat Diet Induced Obese Rats.

Myricetin is a natural flavonol widely occurring in wines. Many beneficial effects of myricetin in alcoholic beverages have been reported before, but never including anti-obesity. In the present study, we fed obese male Sprague-Dawley rats with ethanol solutions containing various concentrations of myricetin and found that myricetin may maintain the food intake while reduce the weight-gain, feed efficiency, level of blood lipids, adipocyte size, and weight and size of the perirenal and epididymal adipose tissues (P < 0.01). Our experiment data also show that the anti-obesity effect may be associated with the upregulation of adropin and β-endorphin levels. Based on the above-described findings, we propose the potential for myricetin-containing alcoholic beverages to be developed into anti-obesity health food.

Exogenous glucagon-like peptide-1 reduces body weight and cholecystokinin-8 enhances this reduction in diet-induced obese male rats

The sites of action regulating meal size (MS) and intermeal interval (IMI) length by glucagon like peptide-1 (7–36) (GLP-1 (7–36)) and cholecystokinin-8 (CCK-8) reside in the areas supplied by the two major branches of the abdominal aorta, celiac and cranial mesenteric arteries. We hypothesized that infusing GLP-1 near those sites reduces body weight (BW) and adding CCK-8 to this infusion enhances the reduction. Here, we measured BW in diet-induced obese (DIO) male rats maintained and tested on normal rat chow and infused with saline, GLP-1 (0.5nmol/kg) and GLP-1+CCK-8 (0.5nmol/kg each) in the aorta once daily for 21days. We found that GLP-1 and GLP-1+CCK-8 decrease BW relative to saline vehicle and GLP-1+CCK-8 reduced it more than GLP-1 alone. Reduction of BW by GLP-1 alone was accompanied by decreased 24-h food intake, first MS, duration of first meal and number of meals, and an increase in latency to first meal. Reduction of BW by the combination of the peptides was accompanied by decrease 24-h food intake, first MS, duration of first meal and number of meals, and increase in the IMI length, satiety ratio and latency to first meal. In conclusion, GLP-1 reduces BW and CCK-8 enhances this reduction if the peptides are given near their sites of action.

Sitagliptin Attenuates Endothelial Dysfunction of Zucker Diabetic Fatty Rats: Implication of the Antiperoxynitrite and Autophagy.

Although the contributions of sitagliptin to endothelial function in diabetes mellitus were previously reported, the potential mechanisms still remain undefined. Our research was intended to explore the underlying mechanisms of protective effects of sitagliptin treatment on endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male lean nondiabetic Zucker rats were used as control and male obese ZDF rats were randomly divided into ZDF and ZDF + sitagliptin groups. The significant decrease in endothelium-dependent relaxation induced by acetylcholine was observed in mesenteric arteries and thoracic aorta rings of ZDF rats. The administration of sitagliptin restored the vascular function effectively. The morphology study showed severe endothelial injuries in thoracic aortas of ZDF rats, and sitagliptin treatment attenuated these changes. The increased malondialdehyde levels and decreased superoxide dismutase activities in serum of ZDF rats were reversed by sitagliptin treatment. Sitagliptin also increased the expression of endothelial nitric oxide synthase and microtubule-associated protein 1 light chain 3 (LC3) and decreased the expression of inducible nitric oxide synthase, 3-nitrotyrosine, and p62 in ZDF rats. After giving Fe (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride porphyrin pentachloride (FeTMPyP, a peroxynitrite [ONOO-] scavenger) or sitagliptin to high-glucose (30 mmol/L, 48 hours) cultured human umbilical vein endothelial cells (HUVECs), the increased levels of Beclin-1 and lysosome-associated membrane protein type 2 were detected. Both FeTMPyP and sitagliptin also significantly increased the number of mRFP-GFP-LC3 dots per cell, suggesting that autophagic flux was increased in HUVECs. Our study indicated that sitagliptin treatment can improve the endothelium-dependent relaxation and attenuate the endothelial impairment of ZDF rats. The protective effects of sitagliptin are possibly related to antiperoxynitrite and promoting autophagy.

Chronic treatment with prebiotics, probiotics and synbiotics attenuated cardiac dysfunction by improving cardiac mitochondrial dysfunction in male obese insulin-resistant rats.

In metabolic syndrome, the composition of gut microbiota has been disrupted, and is associated with left ventricular (LV) dysfunction. Several types of prebiotics, probiotics, and synbiotics have been shown to exert cardioprotection by restoring gut microbiota from dysbiosis and reducing systemic inflammation. However, the effects of prebiotics such as xylooligosaccharides (XOS); probiotics such as Lactobacillus paracasei STII01 HP4, and synbiotics on metabolic and LV function in obese insulin-resistant rats have not been investigated. In this study, we hypothesized that prebiotics and probiotics improve metabolic parameters, heart rate variability (HRV), blood pressure (BP), and LV function by attenuating cardiac mitochondrial dysfunction, systemic inflammation, and oxidative stress, and that synbiotics provide greater efficacy than a single regimen in obese insulin resistance. Rats were fed with either normal diet or high-fat diet (HFD) for 12weeks and then rats in each dietary group were randomly subdivided into four subgroups to receive either a vehicle, prebiotics, probiotics, or synbiotics for another 12weeks. Metabolic parameters, BP, HRV, LV function, cardiac mitochondrial function, systemic inflammation, and oxidative stress were determined. HFD-fed rats had obese insulin resistance with markedly increased systemic inflammatory marker [Serum LPS; ND; 0.6±0.1 EU/ml vs. HFD; 5.7±1.2 EU/ml (p<0.05)], depressed HRV, and increased BP and LV dysfunction [%ejection fraction; ND; 93±2% vs. HFD; 83±2% (p<0.05)]. Prebiotics, probiotics, and synbiotics attenuated insulin resistance by improving insulin sensitivity and lipid profiles. All interventions also improved HRV, BP, LV function [%ejection fraction; HFV; 81±2% vs. HFPE; 93±3%, HFPO; 92±1%, HFC; 92±2% (p<0.05)] by attenuating mitochondrial dysfunction, oxidative stress, and systemic inflammation in obese insulin-resistant rats. Prebiotics, probiotics, and synbiotics shared similar efficacy in reducing insulin resistance and LV dysfunction in obese insulin-resistant rats.

Role of aquaporin-7 in ghrelin- and GLP-1-induced improvement of pancreatic β-cell function after sleeve gastrectomy in obese rats.

Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues as well as for pancreatic insulin secretion. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in β-cells, and AQP12, an aquaporin related to pancreatic damage, in the improvement of pancreatic function and steatosis after sleeve gastrectomy in diet-induced obese rats. Male Wistar obese rats (n=125) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary (pair-fed to the amount of food eaten by sleeve-gastrectomized animals) interventions. The tissue distribution and expression of AQPs in the rat pancreas were analyzed by real-time PCR, western blotting and immunohistochemistry. The effect of ghrelin isoforms and glucagon-like peptide 1 (GLP-1) on insulin secretion, triacylglycerol (TG) accumulation and AQP expression was determined in vitro in RIN-m5F β-cells. Sleeve gastrectomy reduced pancreatic β-cell apoptosis, steatosis and insulin secretion. Lower ghrelin and higher GLP-1 concentrations were also found after bariatric surgery. Acylated and desacyl ghrelin increased TG content, whereas GLP-1 increased insulin release in RIN-m5F β-cells. Sleeve gastrectomy was associated with an upregulation of AQP7 together with a normalization of the increased AQP12 levels in the rat pancreas. Interestingly, ghrelin and GLP-1 repressed AQP7 and AQP12 expression in RIN-m5F β-cells. AQP7 protein was negatively correlated with intracellular lipid accumulation in acylated ghrelin-treated cells and with insulin release in GLP-1-stimulated β-cells. AQP7 upregulation in β-cells after sleeve gastrectomy contributes, in part, to the improvement of pancreatic steatosis and insulin secretion by increasing intracellular glycerol used for insulin release triggered by GLP-1 rather than for ghrelin-induced TG biosynthesis.

The Kv1.3 channel blocker Vm24 enhances muscle glucose transporter 4 mobilization but does not reduce body-weight gain in diet-induced obese male rats

AimsVoltage-gated potassium channels 1.3 (Kv1.3) can be targeted to reduce diet-induced obesity and insulin resistance in mice. Since species-specific differences in Kv1.3 expression and pharmacology have been observed, we tested the effect of Vm24, a high-affinity specific blocker of Kv1.3 channels from Vaejovis mexicanus smithi, on body weight (BW), glucose tolerance and insulin resistance in diet-induced obese rats. Materials and methodsYoung adult male Wistar rats were switched to a high-fat/high-fructose (HFF) diet. Eighteen days later animals were divided in two groups: vehicle and Vm24 group. Subcutaneous injections were applied every other day until sacrifice 2months later. An additional cohort was maintained on standard chow. Key findingsThe HFF diet promoted obesity. Treatment with Vm24 did not alter various metabolic parameters such as food intake, BW gain, visceral white adipose tissue mass, adipocyte diameter, serum glucose, leptin and thyroid hormone concentrations, brown adipose tissue mass or uncoupling protein-1 expression, and insulin tolerance. Vm24 did reduce basal and glucose-stimulated serum insulin concentrations, serum C-peptide concentration, increased QUICKI, and tended to lower HOMA-IR. Vm24 treatment did not change the activation of insulin receptor substrate-1, but enhanced protein-kinase B activation and membrane glucose-transporter 4 (GLUT4) protein levels in skeletal muscle. SignificanceIn conclusion, in male rats, long-term blockade of Kv1.3 channels with Vm24 does not reduce weight gain and visceral adiposity induced by HFF diet; instead, it reduces serum insulin concentration, and enhances GLUT4 mobilization in skeletal muscle.

Hypoxia-inducible Factor 2 Alpha Mediates Exercise-induced Hypothalamic Glucose Sensing

PURPOSE: The hypothalamus controls the energy homeostasis integrating of hormonal and nutritional signals. In this context, glucose plays a critical role in the control of energy balance acting in specific hypothalamic neurons. It has been demonstrated that the lost selective of glucose sensibility in the hypothalamic neurons are related to the hyperphagia and obesity. Recently, the hypoxia-inducible factor 2 alpha (HIF2α) have emerged as regulated important in maintenance of glucose sensibility in hypothalamic neurons. In this context, the maintenance of neuronal HIF2α function can be considerate a determinate strategy for maintenance of lean phenotype. At the same time, the physical exercise is considered a main contributor to the control of body weight and energy expenditure. Thus, sought evaluate the effects of physical exercise on HIF2α protein levels and on glucose sensibility in the hypothalamus of rodents. METHODS:Physical exercise, Western blot and stereotaxic surgery were combined to explore HIF2a protein levels and hypothalamic glucose sensibility. The intracerebroventricular (ICV) injection of glucose was performed to measure the food intake and the quantification of HIF2α pathway in hypothalamus of both lean and obese (diet-induced obesity) male Wistar rats. For statistical analysis were used the ANOVA one-way. RESULTS:We observed the reduction of hypothalamic glucose sensitivity in obese mice, which was accompanied by a lower protein expression of HIF-2α, as well as reduction of prolyl hydroxylases (PHDs) and ubiquitin E3 ligase PVH, product Hippel-Lindau (VHL) gene, when compared to the control group. Interestingly, we found that the exercise restored hypothalamic of HIF-2α expression and glucose sensitivity in obese rats. CONCLUSIONS:Our preliminary results demonstrate that high-fat diet disrupts hypothalamic HIF-2α protein and affects the glucose sensitivity in neurons, contributing with hyperphagia. On the other hand, exercise increased HIF-2α protein levels in the hypothalamus and potentiated glucose sensitivity in obese rats, reducing the food intake.

Beneficial effects of lipidic extracts of saladette tomato pomace and Serenoa repens on prostate and bladder health in obese male Wistar rats

Obesity is associated with increased risk of a number of serious medical conditions, including urological disorders. This study investigated the effect of lipidic extracts of saladette tomato pomace (STP) and Serenoa repens (SR) on the prostate and bladder in a rat obese model induced by high-carbohydrate diet. High-sucrose-fed rats showed higher prostate weight as well as increased contractility and stromal and epithelial hyperplasia in the prostate. Treatment with STP and SR improved contractility and diminished hyperplasia and hypertrophy in the prostate. Obese animals also showed impaired bladder contractility, but neither extract reversed this deterioration. In the histological study, a disarray in the process of smooth muscle cell proliferation with non-parallel fibers was observed; interestingly, treatment with STP and SR led to improvement in this derangement. These findings indicated impaired contractility and hyperplasia in the prostate and bladder of obese rats induced by high sucrose. STP and SR could enhance prostate function by reducing contractility and hyperplasia and improve smooth muscle fiber structure and decrease cell proliferation in the bladder, suggesting their possible health-beneficial effects on lower urinary tract symptoms. © 2017 Society of Chemical Industry.

Oxalobacter formigenes colonization normalizes oxalate excretion in a gastric bypass model of hyperoxaluria

BackgroundHyperoxaluria and oxalate kidney stones frequently develop after Roux-en-Y gastric bypass (RYGB). Oxalobacter formigenes can degrade ingested oxalate. ObjectivesExamine the effect of O. formigenes wild rat strain (OXWR) colonization on urinary oxalate excretion and intestinal oxalate transport in a hyperoxaluric RYGB model. SettingBasic Science Laboratory, United States. MethodsAt 21 weeks of age, 28 obese male Sprague-Dawley rats survived Sham (n = 10) or RYGB (n = 18) surgery and were maintained on a 1.5% potassium oxalate, 40% fat diet. At 12 weeks postoperatively, half the animals in each group were gavaged with OXWR. At 16 weeks, percent dietary fat content was lowered to 10%. Urine and stool were collected weekly to determine oxalate and colonization status, respectively. At week 20, [14 C]-oxalate fluxes and electrical parameters were measured in vitro across isolated distal colon and jejunal (Roux limb) tissue mounted in Ussing Chambers. ResultsRYGB animals lost 22% total weight while Shams gained 5%. On a moderate oxalate diet, urinary oxalate excretion was 4-fold higher in RYGB than Sham controls. OXWR colonization, obtained in all gavaged animals, reduced urinary oxalate excretion 74% in RYGB and 39% in Sham and was further augmented by lowering the percentage of dietary fat. Finally, OXWR colonization significantly enhanced basal net colonic oxalate secretion in both groups. ConclusionsIn our model, OXWR lowered urinary oxalate by luminal oxalate degradation in concert with promotion of enteric oxalate elimination. Trials of O. formigenes colonization and low-fat diet are warranted in calcium oxalate stone formers with gastric bypass and resistant hyperoxaluria.

Roux-en-Y gastric bypass improves glucose homeostasis, reduces oxidative stress and inflammation in livers of obese rats and in Kupffer cells via an AMPK-dependent pathway

Oxidative stress and inflammation are implicated in the pathogenesis of steatohepatitis. We hypothesize that Roux-en-Y gastric bypass reduces oxidative stress and inflammation in the liver of obese rats via activation of AMPK-α. Obese Sprague-Dawley male rats underwent either sham operation or Roux-en-Y gastric bypass. Hepatic TNF-α, NF-κB, IRS-2, PI3 kinase, PKC-ζ, NOX2, and AMPK-α were measured. Mechanistic studies were done in a rat Kupffer cell line (RKC1) that was treated with free fatty acids to mimic lipotoxicity and then transfected with AMPK-α siRNA. Reactive oxygen species, TNF-α, NF-κB, AMPK-α, p-AMPK-α, PPAR-γ, and NOX2 were measured. A t test was used. Roux-en-Y gastric bypass lowered nonfasting serum glucose, improved the glucose tolerance test, and induced IRS2/PI3 kinase interaction. Additionally, Roux-en-Y gastric bypass decreased hepatic NOX2, PKC-ζ, TNF-α expression and activation of NF-κB. Free fatty acids increased reactive oxygen species, TNF-α protein, NOX2 protein, and activated NF-κB. Rosiglitazone attenuated the free fatty acids-induced increase in reactive oxygen species, TNF-α, NOX2, and NF-κB; blocking AMPK-α by siRNA abolished the effects of rosiglitazone. Roux-en-Y gastric bypass exhibits antidiabetic properties and is associated with downregulation of proinflammation genes and oxidative stress in the liver and within Kupffer cells via activation of AMPK-α.

Glibenclamide treatment blocks metabolic dysfunctions and improves vagal activity in monosodium glutamate-obese male rats.

Autonomic nervous system imbalance is associated with metabolic diseases, including diabetes. Glibenclamide is an antidiabetic drug that acts by stimulating insulin secretion from pancreatic beta cells and is widely used in the treatment of type 2 diabetes. Since there is scarce data concerning autonomic nervous system activity and diabetes, the aim of this work was to test whether glibenclamide can improve autonomic nervous system activity and muscarinic acetylcholine receptor function in pre-diabetic obese male rats. Pre-diabetes was induced by treatment with monosodium L-glutamate in neonatal rats. The monosodium L-glutamate group was treated with glibenclamide (2 mg/kg body weight /day) from weaning to 100 days of age, and the control group was treated with water. Body weight, food intake, Lee index, fasting glucose, insulin levels, homeostasis model assessment of insulin resistance, omeostasis model assessment of β-cell function, and fat tissue accumulation were measured. The vagus and sympathetic nerve electrical activity were recorded. Insulin secretion was measured in isolated islets challenged with glucose, acetylcholine, and the selective muscarinic acetylcholine receptor antagonists by radioimmunoassay technique. Glibenclamide treatment prevented the onset of obesity and diminished the retroperitoneal (18%) and epididymal (25%) fat pad tissues. In addition, the glibenclamide treatment also reduced the parasympathetic activity by 28% and glycemia by 20% in monosodium L-glutamate-treated rats. The insulinotropic effect and unaltered cholinergic actions in islets from monosodium L-glutamate groups were increased. Early glibenclamide treatment prevents monosodium L-glutamate-induced obesity onset by balancing autonomic nervous system activity.

Effects of Solanum torvum fruit water extract on hyperlipidemia and sex hormones in high-fat fed male rats

ObjectiveTo study the effect of water extract of Solanum torvum (S. torvum) on blood lipid and sex hormone levels in high-fat diet (HFD) fed male rats. MethodsMale Wistar rats were maintained on a standard diet or HFD for 10 weeks. During the last 4 weeks, the standard diet groups received distilled water or S. torvum (400 mg/kg) and the HFD groups received distilled water or S. torvum (100, 200 and 400 mg/kg). Body weight, lipid profiles, sex hormone, internal organs weight and liver histopathology were all measured. Moreover, kidney function was evaluated using blood urea nitrogen and creatinine levels, and liver function by the levels of aspartate aminotransferase and alanine aminotransferase. ResultsThe result showed that rats in the HFD control group had increased body weight and hyperlipidemia, but had decreased levels of both testosterone and estradiol. When receiving the S. torvum extract at a dose of 100 mg/kg, treated rats had significantly increased sex hormone levels of both types, and decreased total cholesterol levels, and at a dose of 200 mg/kg, treated rats had significantly decreased levels of triglyceride. Long term administration of the S. torvum did not produce any toxic signs in livers and kidneys. Pathological examinations of livers showed lipid accumulation in the HFD group, but the treatment of S. torvum slightly reduced lipid deposition in liver tissue. ConclusionsS. torvum extract can reverse the level of sex hormones to their normal level and reduce serum cholesterol in HFD-induced obese male rats. Furthermore, the long term oral administration of S. torvum extract is harmless.

Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain μ-opioid Receptor Availability in Diet-Induced Obese Male Rats.

Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [11C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [11C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.