Animal Model Of Metabolic Syndrome Research Articles

Deficiency of ASGR1 Alleviates Diet-Induced Systemic Insulin Resistance via Improved Hepatic Insulin Sensitivity.

Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown. The constructed ASGR1 knockout mice and ASGR1-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro. ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis. The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.

Cardiorenal protective effects of extracts of bitter leaf (Vernonia amygdalina) in animal model of metabolic syndrome

Every year, metabolic syndrome and cardiorenal diseases cause many deaths worldwide. African bitter leaf (Vernonia amygdalina) is known for its numerous therapeutic effects. Potentially, it can lower plasma lipid and glucose levels, which, in turn, may improve the condition of patients with the abovementioned diseases. This research featured the antihyperlipidemic and antihyperglycemic effects of methanol extract of V. amygdalina in an animal model of metabolic syndrome.
 Twenty albino rats were divided into four groups. Groups A to C were orally administered with ghee (3 mL/kg) + high-cholesterol diet (500 mg/kg) + high-sugar diet (10 mL/kg) to induce metabolic syndrome. Group A served as negative control and received no treatment with bitter leaf methanol extract. Groups B and C received 200 and 400 mg/kg of V. amygdalina methanol extract, respectively. Group D received no administration. The cardiorenal injuries and alterations in blood lipids and sugar levels wereassessed via various biochemical analyses.
 The combination of ghee + high-cholesterol diet + high-sugar diet triggered a significant elevation of creatine kinase myocardial band, lactate dehydrogenase, aspartate aminotransferase, triglycerides, total cholesterol, low density lipoprotein-cholesterol, glucose, urea, creatinine, and potassium levels. The histopathological results agreed with the biochemical findings. However, the treatment with 200 and 400 mg/kg of V. amygdalina methanol extract was able to inhibit the adverse alterations causing a dosedependent significant antihyperlipidemic and antihyperglycemic effect (p < 0.05).
 Bitter leaf (V. amygdalina) demonstrated cardiorenal protective effects and may be used to manage metabolic syndrome.

Molecular Study of the Protective Effect of a Low-Carbohydrate, High-Fat Diet against Brain Insulin Resistance in an Animal Model of Metabolic Syndrome.

Brain insulin resistance is linked to metabolic syndrome (MetS). A low-carbohydrate, high-fat (LCHF) diet has been proposed to have a protective effect. Therefore, this study aimed to investigate the brain insulin resistance markers in a rat animal model of MetS and the protective effects of the LCHF diet. Four groups of male rats (10/group) were created. Group I (Control) was fed a regular diet. Groups II-IV were injected with dexamethasone (DEX) to induce MetS. Group II received DEX with a regular diet. Group III (DEX + LCHF) rates were fed a low-carbohydrate, high-fat diet, while Group IV (DEX + HCLF) rats were fed a high-carbohydrate, low-fat (HCLF) diet. At the end of the four-week experiment, HOMA-IR was calculated. Moreover, cerebral gene expression analysis of S-100B, BDNF, TNF-α, IGF-1, IGF-1 R, IGFBP-2, IGFBP-5, Bax, Bcl-2, and caspase-3 was carried out. In the DEX group, rats showed a significant increase in the HOMA-IR and a decrease in the gene expression of IGF-1, IGF-1 R, IGFBP-2, IGFBP-5, BDNF, and Bcl2, with a concomitant rise in S100B, TNF-α, Bax, and caspase-3. The LCHF diet group showed a significantly opposite effect on all parameters. In conclusion, MetS is associated with dysregulated cerebral gene expression of BDNF, S100B, and TNF-α and disturbed IGF-1 signaling, with increased apoptosis and neuroinflammation. Moreover, the LCHF diet showed a protective effect, as evidenced by preservation of the investigated biochemical and molecular parameters.

The Effect of Baekhogainsam-tang on Metabolism through Modulation of the Gut Microbiota and Gene Expression in High-Fat Diet Induced Metabolic Syndrome Animal Model

The Effect of <i>Baekhogainsam-tang</i> on Metabolism through Modulation of the Gut Microbiota and Gene Expression in High-Fat Diet Induced Metabolic Syndrome Animal Model

1678-P: B6-Alms1-del Mice, a Metabolic Syndrome Animal Model, Shows Semaglutide Benefits on Obesity, Hyperglycemia, and NAFL

Metabolic syndrome is a cluster of conditions that occur together, increasing the risk of heart disease, stroke and type 2 diabetes. These conditions include obesity, hyperglycemia, hypertension, hyperlipidemia. Leptin and leptin receptor mutant mice, ob/ob and db/db, are two classic metabolic syndrome animal model. However, the transient hyperglycemia of ob/ob and severe hyperglycemia induced premature death of db/db limit the application of these two models. To fill the gap, GemPharmatech developed a metabolic disorder model based on the mutation of Alms1 gene in mice (B6-Alms1-del mice). B6-Alms1-del mice gradually developed obesity from 8 weeks old with chow diet, accompanied by hyperglycemia, glucose and insulin intolerance, dyslipidemia and impaired liver function. Moreover, B6-Alms1-del mice developed severe non alcoholic fatty liver spontaneously as early as 21 weeks old and no premature death was observed around 5~8 months of ages. As B6-Alms1-del mice copied major features of metabolic syndrome, we further tested whether B6-Alms1-del mice could response to the positive drug semaglutide, an agonist of GLP-1R. 16 weeks old B6-Alms1-del mice were treated with vehicle and semaglutide for 5 weeks, respectively. Our results indicate that semaglutide lead to benefit on metabolic syndrome, including body weight control, improvement in hyperglycemia, hyperlipidemia, liver injury and hepatic steatosis. In conclusion, we have established a metabolic syndrome animal model that develop clinically relevant metabolic phenotypes and overcome the limitation of ob/ob and db/db. Furthermore, B6-Alms1-del mice responds to the approval anti-obesity drug semaglutide, which provide a useful model to assess the efficacy of novel metabolic syndrome therapies. Disclosure Z.Chen: None. M.Gao: None. X.Zhao: None. Z.Li: None. J.Zhao: None. C.Ju: None. X.Gao: None.

Effects of Punica granatum L. peel extract supplementation on body weight, cardiac function, and haematological and biochemical parameters in an animal model of metabolic syndrome.

Metabolic syndrome (MetS) is a cluster of pathological conditions well described in humans but still investigated insufficiently in animals. A novel approach in its management is the utilisation of nutrients from natural sources. Recent studies suggested that phenolic compounds from pomegranate peel could be a promising dietary intervention for MetS. This study evaluated the potency of polyphenol-rich pomegranate peel extract (EPP) in mitigating some MetS components in an animal model. Zucker diabetic fatty rats (with an fa/fa missense mutation in the Lepr leptin receptor gene) and their healthy counterparts (fa/+) as controls were fed a high-calorie diet to induce MetS and supplemented with EPP at two doses: 100 mg/kg body weight (b.w.) and 200 mg/kg b.w. The extract was administered for eight weeks. The rats' body weights were monitored twice per week, and blood samples were taken before EPP administration after four weeks and eight weeks of study. Echocardiography measurement was performed at the beginning and at the end of the study. The extract restrained the dynamic of weight gain. A cardioprotective effect of the highest dose of EPP supplementation was manifested in a relative decrease in heart rate and improved mid-fractional shortening, representing myocardial contractility. No improvement in fasting blood glucose or lipid profile was observed. Pomegranate peel extract possesses beneficial health properties that could be useful in dietary intervention in MetS. However, its bioavailability still requires further investigation in clinical trials in humans and animals suffering from endocrine and metabolic disorders.

Punica granatum L. Extract Shows Cardioprotective Effects Measured by Oxidative Stress Markers and Biomarkers of Heart Failure in an Animal Model of Metabolic Syndrome.

Metabolic syndrome (MetS) significantly increases the risk of cardiovascular diseases (CVD), a leading cause of death globally. The presented study investigated the cardioprotective role of dietary polyphenols found in pomegranate peels in an animal model of metabolic syndrome. Zucker diabetic fatty rats (ZDF, MetS rats, fa/fa) were supplemented with polyphenol-rich pomegranate peel extract (EPP) at two dosages: 100 mg/kg BW and 200 mg/kg BW. The extract was administered for 8 weeks. The effect of ethanolic peel extract on the concentration of oxidative stress markers (CAT, SOD, MnSOD, GR, GST, GPx, TOS, SH, and MDA), biomarkers of heart failure (cTnI, GAL-3), and alternations in tissue architecture was assessed. The results showed a significant increase in SH concentration mediated via EPP supplementation (p < 0.001). Treatment with a 100 mg/kg BW dosage reduced the TOS level more efficiently than the higher dose. Interestingly, the CAT and GST activities were relevantly higher in the MetS 100 group (p < 0.001) compared to the MetS control. The rats administered EPP at a dose of 200 mg/kg BW did not follow a similar trend. No differences in the GR (p = 0.063), SOD (p = 0.455), MnSOD (p = 0.155), and MDA (p = 0.790) concentration were observed after exposure to the pomegranate peel extract. The administration of EPP did not influence the cTnI and GAL-3 levels. Histology analysis of the heart and aorta sections revealed no toxic changes in phenolic-treated rats. The findings of this study prove that the extract from pomegranate peels possesses free radical scavenging properties in the myocardium. The effect on alleviating ventricular remodeling and cardiomyocyte necrosis was not confirmed and requires further investigation.

Changes in hepatic thiol contents and regulation of glutathione S-transferase by high-fructose diet: Effects of kefir and some probiotic bacteria

In this study, thiol/disulfide homeostasis in the liver tissues of high-fructose-fed rats was investigated in conjunction with the changes in the main hepatic detoxification enzyme, glutathione S-transferase (GST). Additionally, the effects of well-known probiotics namely Kefir, Lactobacillus helveticus, and Lactobacillus plantarum supplementation on the thiol/disulfate contents and GST activity and gene expression levels were analyzed. Fructose, administered as a 20% solution in drinking water for 15 weeks, developed an animal model of metabolic syndrome in male Wistar rats. Kefir, L. helveticus, and L. plantarum supplementations were given by gastric gavage once a day during the final 6-weeks. The changes in hepatic GST were determined with kinetic-optimized spectrophotometric enzyme assays and qRT-PCR. Total thiol, native thiol, and disulfide levels were analyzed using (5,5-dithio-bis-(2-nitrobenzoic acid) as a chromogenic agent. High-fructose consumption reduced total and native thiol contents while increasing disulfide levels in the liver tissues of rats. Kefir and L. plantarum normalized the thiol levels and all probiotics reduced disulfide contents. High fructose augmented total GST activity but reduced the GST-Mu isoform. L. helveticus and L. plantarum normalized the total and GST-Mu activity, respectively. These results demonstrated a shift toward disulfide formation in the hepatic tissues of rats fed with high fructose. A possible reason would be the increase in total GST activity that uses the free glutathione, the main native thiol source in cells, as a substrate. Besides, probiotics such as Kefir, L. helveticus, and L. plantarum have an improving effect on thiol/disulfide homeostasis as well as main detoxification enzymes.&#x0D;

Carbonylated Proteins as Key Regulators in the Progression of Metabolic Syndrome.

Based on the known role of oxidative stress in the pathogenesis and progression of metabolic syndrome, we used two-dimensional gel electrophoresis with immunochemical detection of protein carbonyls (2D-Oxyblot) to characterize the carbonylated proteins induced by oxidative stress in spontaneously hypertensive rats/NDmcr-cp (CP), an animal model of metabolic syndrome. We also profiled the proteins that showed change of expression levels in their epididymal adipose tissue at the pre-symptomatic (6-week-old) and the symptomatic (25-week-old) stages of the metabolic syndrome. Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF MS) was used to analyze proteins extracted from the epididymal adipose tissue. The up-regulated proteins identified at the pre-symptomatic stage were mainly associated with ATP production and redox reaction, while the down-regulated proteins found at the symptomatic stage were involved in antioxidant activity and the tricarboxylic acid (TCA) cycle. Further analysis using the 2D-Oxyblot showed significantly high carbonylation levels of gelsolin and glycerol-3-phosphate dehydrogenase [NAD+] at the symptomatic stage. These results suggest that reduced antioxidant capacity underlies the increased oxidative stress state in the metabolic syndrome. The identified carbonylated proteins, including gelsolin, are potential targets that may act as key regulators in the progression of the metabolic syndrome.

PS-B07-6: L-ARGININE SUPPLEMENTATION SUBSTANTIALLY ATTENUATES HYPERTENSION BUT NOT CARDIAC INJURY IN RATS WITH METABOLIC SYNDROME

Objective: L-arginine is not only a building block for protein but also a physiological substrate for the synthesis of nitric oxide (NO) and plays a regulatory role in signal transduction pathways in cells. Dietary L-arginine supplementation reduced fat mass both in Zucker diabetic fatty rats and in diet-induced obese rats. However, little is known about the effects of L-arginine on cardiac morphology and function in metabolic disorders. We have now examined the effects of L-arginine on cardiac pathology in DahlS.Z-Leprfa/Leprfa (DS/obese) rats, an animal model of metabolic syndrome (MetS). Design and method: DS/obese rats and their homozygous lean (DahlS.Z-Lepr+/Lepr+, or DS/lean) littermate controls were fed a purified control diet and were supplemented with 0.50% L-arginine-HCl or 0.85% L-alanine (isonitrogenous control) in drinking water from 13 to 17 weeks of age. Results: L-arginine supplementation did not affect body weight, visceral and subcutaneous fat mass, insulin resistance, or food and water intake in DS/obese rats, but substantially alleviated hypertension. However, left ventricular (LV) and cardiomyocyte hypertrophy and the upregulation of myocardial fetal-type gene expression, macrophage infiltration in the heart, and increased perivascular and interstitial fibrosis of the LV myocardium and the upregulation of fibrosis-related gene expression were not improved by such intervention. Additionally, L-arginine did not ameliorate impairments of Doppler- or micromanometer-derived indices of LV diastolic function. None of these parameters were influenced by L-arginine supplementation in DS/lean rats. Conclusions: L-arginine supplementation substantially ameliorated hypertension but did not attenuate LV remodeling or diastolic dysfunction in this model of MetS. These data suggest that in addition to its role as a precursor of NO, L-arginine may play a role as a functional amino acid that modulates growth and inflammation.

Animal Model for Diabetes Co-existing with Metabolic Syndrome

Metabolic syndrome includes diverse disorders together with truncal obesity, dyslipidemia, high blood pressure, and hyperglycemia. The occurrence of metabolic syndrome is growing globally. The unfavorable results of metabolic syndrome have brought on research efforts to broaden new interventions to reduce the weight of the healthcare system. Because of its multifactorial nature, it may be hard to pick out the best experimental version that high-quality represents the pathophysiology of human metabolic syndrome. Many animal models have evolved and been studied to clarify the molecular mechanisms and useful modifications associated with metabolic sicknesses. Properly characterized and clinically applicable experimental models are taken into consideration as crucial tools for testing new pills and information on their molecular foundation, their pathogenesis, and mechanism of movement. In this review, we collate and discuss the various animal models of metabolic syndrome and the suitability of diabetes co-existing with metabolic syndrome animal models for research also be discussed to provide the readers with a comprehensive overview of the selection of the best animal models to meet their research purpose. Keyword:Animal model, Metabolic syndrome, High fat diet, Rat

RF36 | PSUN101 Liver and Adipose Tissue Effects of Triiodothyronine Treatment in an Animal Model of Metabolic Syndrome

Abstract Introduction Metabolic syndrome (MS) associates to obesity and non-alcoholic fatty liver disease (NAFLD). Besides its high and rising prevalence, the therapeutical options are scarce. Studies show that thyroid hormones (TH) may ameliorate hepatic function and hepatic and extra-hepatic lipid deposition. Aim To evaluate the effects of triiodothyronine (T3) treatment in high and low dose on the liver and adipose tissue of an animal model of metabolic syndrome (ZSF1 rats). Material and methods Four groups of animals were evaluated: 1) ZSF1 lean rats (Ln, used as controls; n=8); 2) untreated ZSF1 obese rats (Ob; animal model of MS; n=10); 3) ZSF1 obese rats treated with high dose T3 (hT3; initially 0.04mg/mL and 0.06mg/mL after 4 weeks; n=5); 4) ZSF1 obese rats treated with low dose T3 (lT3; 0.03mg/mL; n=5). We performed anthropometric and oral glucose tolerance testing (OGTT). Tissues and blood were collected at the 24th week of age for histological evaluation and assessing the levels of thyroid hormones. Results The animals from hT3 and lT3 groups had similar weights and both were significantly heavier (tibial length/weight ratio of 14.7±0.6 and 14.1±0.7g/mm respectively) than Ln (10.7±0.6g/mm, p&amp;lt;0.01). The rats from lT3 group were also significantly lighter than Ob (15.3±1.0g/mm, p=0.042). Fasting glucose of hT3 (118.6±36.0mg/dL) was lower comparing to Ob (228.1±58.6mg/dL, p&amp;lt;0.01) and to lT3 (207.2±69.8mg/dL, p=0.048) and similar to Ln (82.1±9.1mg/dL, p=1.00). The evaluation of the area under the curve (AUC) of OGTT is in agreement with these results. The histological evaluation of the liver showed a ratio between lipids and surrounding tissue significantly lower in the treated groups (hT3 0.35±0.1 and lT3 0.34±0.1) compared to Ob (0.89±0.2, p&amp;lt;0.01) and similar to Ln (0.14±0.1, p=0.106 and p=0.124, respectively). The ratio between glycogen and surrounding tissue was not different between treated animals and either Ob or Ln. Concerning the adipose tissue, adipocyte area was similar between treated animals (hT3 7435±1031mm2 and lT3 6899±554mm2, p=1.00) and was significantly lower compared to Ob (9037±789mm2, p&amp;lt;0.01) and higher compared to Ln (2771±754mm2, p&amp;lt;0.01). The area of fibrosis was similar between hT3 and lT3 (7.7±1.1mm and 6.6±0. 5mm, respectively, p=1. 00), higher when comparing both groups with Ln (2.4±1.3mm, p&amp;lt;0.01) and lower when comparing both groups with Ob (13.5±2.2mm, p&amp;lt;0.01). Conclusion Treatment of obese ZSF1 animals with T3 improved the glycemic profile, and lipid and fibrous deposition in the liver and adipose tissue. The usage of low dose T3 does not seem different from high dose concerning these effects and might be associated with fewer adverse events. TH may, in the future, become an option when treating patients with MS and NAFLD. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:42 p.m. - 12:47 p.m.

Back Cover: Gut Microbes Are Associated with the Vascular Beneficial Effects of Dietary Strawberry on Metabolic Syndrome‐Induced Vascular Inflammation

Mol. Nutr. Food Res. 2022, 66, 202200112 DOI: 10.1002/mnfr.202200112 In article 2200112, Pon Velayutham Anandh Babu and co-workers show that dietary supplementation of strawberries reduces vascular complications in an animal model of metabolic syndrome, which is associated with changes in gut microbiota composition.

OR19-2 Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF) with Low and High Dose of Triiodothyronine: an Animal Model of Metabolic Syndrome with HFpEF

Abstract Introduction Low levels of triiodothyronine (T3) are common in patients with heart failure (HF). It has been proposed that the decreased levels of T3 contribute to metabolic and cardiac dysfunction in HF. We aimed to evaluate the effects of treatment with low dose and high dose of T3 in an animal model of HF with preserved ejection fraction (HFpEF). Materials and Methods We evaluated four groups: ZSF1 Lean (Lean-Ctrl, n=8), ZSF1 obese (rat model of metabolic syndrome with HFpEF, HFpEF-Ctrl, n=13), ZSF1 obese supplemented with a replacement dose of T3 (initially 0.04mg/ml, increased to 0.06mg/ml after 4 weeks; HFpEF-T3high, n=8), and ZSF1 Obese supplemented with a low-dose of T3 (0.03mg/mL; HFpEF-T3low, n=8). T3 was supplemented in drinking water from week 13 to 24. The animals were submitted to anthropometric and metabolic evaluation, echocardiography, VO2max evaluation, hemodynamic evaluation, single cardiomyocyte evaluation, and myocardial tissue collection at 24 weeks. Results HFpEF-Ctrl animals had lower serum and myocardial thyroid hormone levels than Lean-Ctrl. Treatment with low dose and high dose of T3 did not correct serum T3 levels, but increased myocardial T3 levels, with normalization of myocardial T3 levels in the HFpEF-T3high group. In comparison to HFpEF-Ctrl, body weight was significantly decreased in HFpEF-T3low and HFpEF-T3high groups (616±39g, 572±24g and 535±18g respectively, p&amp;lt;0.001). An improvement in glucose metabolism was observed only in HFpEF-T3high, with a decreased AUC of glucose during OGTT and insulin tolerance test. Both treated groups presented an improvement in diastolic function (with decreased isovolumetric relaxation time) and systolic function (with increased peak systolic velocity and decreased ejection time) comparing to HFpEF-Ctrl. These results were supported by enhanced Ca2+ transients during diastole and sarcomere relaxation. Comparing with HFpEF-Ctrl, animals treated with T3 had higher myocardial expression of the calcium transporter RYR2, of the transcriptional coactivator PGC-1α, and of the α-myosin heavy chain (MHC), with a lower expression of β-MHC. VO2max was improved with low-dose and high-dose T3 compared with HFpEF-Ctrl. Comparing with HFpEF-Ctrl, heart rate was increased with high-dose (277.9±30.2 vs 313.5±35.8, p=0.049) but not significantly with low-dose (277.9±30.2 vs 299.8±30.9 bpm, p=0.13). Mortality was increased in the HFpEF-T3high comparing with the other groups (no animals died during the protocol in the Lean-Ctrl, HFpEF-Ctrl and HFpEF-T3low groups; three animals had sudden death in the HFpEF-T3high group). Conclusion Treatment with T3 improves metabolic function, myocardial calcium handling, diastolic and systolic function, and exercise capacity in this animal model of HFpEF. While the low dose was well tolerated and safe, the high dose was associated with increased heart rate and a higher risk of sudden death. Modulation of thyroid hormones may be a potential therapeutic target in HFpEF; however such approaches must take into account a narrow therapeutic window of T3 in HFpEF. Presentation: Monday, June 13, 2022 11:15 p.m. - 11:30 a.m.

Efficacy of aqueous extract of flower of Edgeworthia gardneri (Wall.) Meisn on glucose and lipid metabolism in KK/Upj-Ay/J mice.

To observe the effects of the flower of Edgeworthia gardneri (Wall.) Meisn (EWM) on glucose and lipid metabolism in KK/upj-Ay/J (KKAy) mice and investigate the possible mechanism of EWM in the liver of KKAy mice by transcriptome analysis. Forty KKAy mice were fed a high-sugar and high-fat diet for 3 weeks to establish the animal model of metabolic syndrome. After 5 weeks of continuous administration of EWM, serum high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), total cholesterol (TC), and free fatty acids (FFA) were detected by radioimmunoassay. Serum fasting insulin (Fins) and adiponectin levels were measured by enzyme-linked immunosorbent assay. Liver tissue fixed with paraformaldehyde was stained with hematoxylin-eosin and oil red O. Transcriptome analysis was used to evaluate the liver tissue. The expressions of lipoprotein lipase (LPL), peroxisome proliferator-activated receptor-γ (PPARγ), adenosine 5'-monophosphate-activated protein kinase (AMPK), sterol regulatory element binding protein-1c (SREBP-1c), and fatty acid synthase (Fas) mRNA and protein in liver tissue were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. EWM slightly reduced FBG and Fins in KKAy mice. Furthermore, EWM was able to downregulate serum LDL, TG, TC, and FFA and upregulate the expression of serum HDL and adiponectin. Transcriptome analysis revealed the following differential pathways: the peroxisome proliferator-activated receptor (PPAR) signaling pathway and the AMPK signaling pathway. RT-PCR and western blot analysis detected the associated genes and proteins. In addition, EWM was able to upregulate the expression of AMPK and downregulate the expression of PPARγ, SREBP1c, and Fas mRNA and protein and upregulate the expression of LPL mRNA. EWM can alleviate lipid metabolism disorders and to some extent improve glucose metabolism disorders in KKAy mice. These effects may be related to regulating PPARγ/LPL and activating the AMPK/SREBP1c/Fas pathway.

Pharmacological inhibition of the lipid phosphatase PTEN ameliorates heart damage and adipose tissue inflammation in stressed rats with metabolic syndrome.

Phosphatidylinositol 3‐kinase (PI3K) signaling promotes the differentiation and proliferation of regulatory B (Breg) cells, and the lipid phosphatase phosphatase and tensin homolog deleted on chromosome 10 (PTEN) antagonizes the PI3K–Akt signaling pathway. We previously demonstrated that cardiac Akt activity is increased and that restraint stress exacerbates hypertension and both heart and adipose tissue (AT) inflammation in DS/obese rats, an animal model of metabolic syndrome (MetS). We here examined the effects of restraint stress and pharmacological inhibition of PTEN on heart and AT pathology in such rats. Nine‐week‐old animals were treated with the PTEN inhibitor bisperoxovanadium‐pic [bpV(pic)] or vehicle in the absence or presence of restraint stress for 4 weeks. BpV(pic) treatment had no effect on body weight or fat mass but attenuated hypertension in DS/obese rats subjected to restraint stress. BpV(pic) ameliorated left ventricular (LV) inflammation, fibrosis, and diastolic dysfunction as well as AT inflammation in the stressed rats. Restraint stress reduced myocardial capillary density, and this effect was prevented by bpV(pic). In addition, bpV(pic) increased the proportions of Breg and B‐1 cells as well as reduced those of CD8+ T and B‐2 cells in AT of stressed rats. Our results indicate that inhibition of PTEN by bpV(pic) alleviated heart and AT inflammation in stressed rats with MetS. These positive effects of bpV(pic) are likely due, at least in part, to a reduction in blood pressure, an increase in myocardial capillary formation, and an altered distribution of immune cells in fat tissue that result from the activation of PI3K–Akt signaling.

Administration Time Significantly Affects Plasma Bioavailability of Grape Seed Proanthocyanidins Extract in Healthy and Obese Fischer 344 Rats.

Phenolic compounds are bioactive molecules that are associated with several health benefits. Metabolization and absorption are the main determinants of their bioavailability and bioactivity. Thus, the study of the factors that modulate these processes, such as sex or diet is essential. Recently, it has been shown that biological rhythms may also play a key role. Hence, the aim of this study is to evaluate if the bioavailability of a grape proanthocyanidin extract (GSPE) is affected by the administration time in an animal model of metabolic syndrome (MetS). Female and male Fischer 344 rats are fed either a standard or a cafeteria diet (CAF) for 9 weeks, and an oral dose of GSPE (25mg kg-1 ) is daily administered either at 8:00 am (zeitgeber time (ZT)-0) or at 8:00 pm (ZT-12) during the last 4 weeks. Plasma phenolic compounds are then quantified by liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Phase-II and gut microbiota-derived phenolic metabolites are affected by ZT in all conditions or only in obese rats, respectively. CAF feeding affected the bioavailability of phenolic acids and free flavan-3-ols. Differences due to sex are also observed. These findings demonstrate that ZT, diet, and sex are key factors influencing phenolic compounds bioavailability.

Abstract 11502: Elevations in Proinflammatory Cytokines Il-1β and Il-12 in the Transgenic (mren2)27 Rat: A Clinically-Relevant Animal Model of Metabolic Syndrome

Introduction: Spontaneous intracerebral hemorrhage (ICH) accounts for 10-15% of strokes and carries a 40% mortality rate within one month. Neuroinflammation plays a key role in secondary brain injury after ICH and inflammatory pathways may represent important therapeutic targets. A major obstacle in developing novel therapeutics is the lack of a translatable animal model that recapitulates the comorbidities of patient’s that suffer from ICH. Hypertension, diabetes, and obesity are components of the metabolic syndrome often seen in ICH patients, and may modulate the neuroinflammatory response to ICH. Thus, we aimed to characterize peripheral markers of systemic inflammation in a transgenic hypertensive (mRen2)27 rat model of metabolic syndrome. Methods: Serum proinflammatory cytokines IL-1β and IL-12 were measured using ELISA in naïve male and female (mRen2)27 (n=15) and healthy SD rats at 32 weeks of age (n=14). Systolic blood pressure (SBP) was measured by tail-cuff plethysmography. Statistical analyses of group differences were conducted using two-sample t-tests. Results: SBP (mm Hg) was significantly higher in the (mRen2)27 transgenic rats compared to SD rats, in both males (195 ± 4, n=8 vs. 125 ± 4, n=6, p&lt; 0.05) and females (183±7, n=7 vs. 114±10, n=8, p&lt; 0.05). Female (mRen2)27 rats had significantly higher serum concentrations (pg/mL) of IL-12 (1073±47, n=7 vs. 438±101, n=8, p&lt; 0.05) and IL-1β (pg/mL) (11±3, n=7;. 4±1 , n=8, p&lt; 0.05). Similarly, male (mRen2)27 rats had significantly higher levels of IL-12 compared to SD rats (825±58 , n=8 v. 582±90 , n=6, p&lt; 0.05). IL-12 levels were higher in mRen female rats compared with males (1073±47, n=7 v. 825±58 , n=8, p&lt; 0.05). Serum levels of IL-1β was not significantly different between male SD and (mRen2)27 rats. Conclusion: Compared to healthy SD rats, the pro-inflammatory cytokines IL-1β and IL-12 are elevated in a clinically-relevant animal model of spontaneous hypertension. These findings simulate human studies that have linked cardiometabolic disease with elevated levels of pro-inflammatory cytokines. Future studies using this animal model will seek to further characterize changes in perihematomal and peripheral levels of proinflammatory and inflammation-resolving cytokines following ICH.

Abstract P171: Comparison Of Modulation Of Renal Arterial Tone By Perivascular Adipose Tissue Between Two Animal Models Of Metabolic Syndrome

Sex differences have recently been noticed in the regulation of arterial tone by perivascular adipose tissue (PVAT). In SHRSP.Z- Lepr fa /IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS), we demonstrated that mesenteric and renal PVAT in female rats consistently have an enhancing effect on vasodilation at 23 weeks, an age by which the effect of PVAT is impaired in the male rats. This could explain the sex differences in the prevalence of cardiovascular complications in patients with MetS. Therefore, we determined whether the sex difference in PVAT response also occurs in another animal model of MetS, SHR/NDmcr-cp (SHR-cp) rats.Renal arteries were isolated from male and female 23-week-old SHR-cp rats, and ring preparations with and without PVAT were made. After a stable contraction was obtained by phenylephrine administration, vasodilation in response to acetylcholine was examined using organ bath methods.Vasodilation in arteries without PVAT from female rats was smaller than that in arteries without PVAT from male rats, and presence of PVAT in arteries from female rats increased vasodilation to the same level as that observed in arteries without PVAT from male rats. Furthermore, renal PVAT in male rats was shown to have an enhancing effect on vasodilation.The present study did not identify sex differences in renal PVAT-mediated modulation in SHR-cp rats because the enhancing effects of PVAT did not disappear in male SHR-cp rats, in contrast to that observed in male SHRSP.ZF rats at the same age. The difference in PVAT response in male rats between two MetS models may be due to differences in the severity of MetS symptoms, especially blood pressure, between the models.

Comparing the Effects of Febuxostat and Allopurinol in an Animal Model of Metabolic Syndrome

Introduction: Recent studies highlighted the association of hyperuricemia and metabolic syndrome (MS). The aim of this study was to compare the beneficial effects of febuxostat versus allopurinol on the biochemical changes that occur in MS. Methods: Forty adult male Sprague Dawley albino rats were used in the study. Insulin resistance and MS were induced by administration of a high-fructose diet for 8 weeks. Follow-up of changes in weight, blood pressure, serum biochemical parameters, serum antioxidant catalase, and glutathione peroxidase activities was done. At the end of the study, animals were sacrificed, and the thoracic aorta was isolated for in vitro study of the endothelial integrity. Results: Allopurinol and febuxostat treatment induced significant reduction in body weight, systolic blood pressure, blood glucose, insulin, lipids, and improved kidney functions and endothelial integrity compared to nontreated rats. Febuxostat was more effective than allopurinol in normalizing serum fasting glucose, uric acid, catalase, and glutathione peroxidase activities. Conclusion: Xanthine oxidase inhibitors ameliorated the effects of MS. Febuxostat was mildly superior to allopurinol in lowering serum fasting glucose, lipids, uric acid, and antioxidant enzyme activities.