Combination Of High-fat Diet Research Articles

Extra-virgin olive oil ameliorates high-fat diet-induced seminal and testicular disorders by modulating the cholesterol pathway.

Rabbits are sensitive to dietary cholesterol and rapidly develop hypercholesterolemia, leading to prominent subfertility. Sterol regulatory element-binding protein isoform 2 drives the intracellular cholesterol pathway in many tissues, including the testicles. Its abnormal regulation could be the mainly responsible for the failure of suppressing cholesterol synthesis in a cholesterol-enriched environment, ultimately leading to testicular and seminal alterations. However, extra-virgin olive oil consumption has beneficial properties that promote lowering of cholesterol levels, including the recovery of seminal parameters altered under a high-fat diet. Our goal was to investigate the effects of high-fat diet supplementation with extra-virgin olive oil at the molecular level on rabbit testes, by analyzing sterol regulatory element-binding protein isoform 2 protein and its corresponding downstream effectors. During 12months, male rabbits were fed a control diet, high-fat diet, or 6-month high-fat diet followed by 6-month high-fat diet plus extra-virgin olive oil. Serum lipids, testosterone levels, bodyweight, and seminal parameters were tested. The mRNA and protein levels of sterol regulatory element-binding protein isoform 2, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, and low-density lipoprotein receptor were determined by semi-quantitative polymerase chain reaction and Western blotting techniques. The expression pattern of sterol regulatory element-binding protein isoform 2 protein in the rabbit testicles was studied by indirect immunofluorescence. In addition, testicular cholesterol was detected and quantified by filipin staining and gas chromatography. The data showed that the addition of extra-virgin olive oil to high-fat diet reduced testicular cholesterol levels and recovered the expression of sterol regulatory element-binding protein isoform 2, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, and low-density lipoprotein receptor initially altered by the high-fat diet. The combination of high-fat diet with extra-virgin olive oil encourages testicular recovery by modifying the expression of the enzymes related to intracellular cholesterol management.

Alfuzosin ameliorates diabetes by boosting PGK1 activity in diabetic mice

AimsDiabetes mellitus (DM) has become a global problem, causing a huge economic burden. The purpose of this study is to find a new potential method and mechanism for the treatment of DM. Main methodsThe oxidation, glycation and insulin resistance cell models were built to screen the potential anti-diabetic chemicals. Then the DM mice were induced by the combination of high-fat diet (HFD) and intraperitoneal injection of streptozotocin (50 mg/kg) for five days. The alfuzosin (1.2 mg/kg) was administered by intraperitoneal injection once daily for sequential 12 weeks. Fasting blood glucose, blood lipid, oxidative stress and key markers of glucose metabolism were detected. PGK1/AKT/GLUT4 pathway related proteins were analyzed by Western blot. Key findingsAlfuzosin ameliorated oxidative stress, glycative stress and insulin resistance in HepG2 cells. Further, in a high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mouse model, alfuzosin reduced fasting blood glucose, improved insulin sensitivity. Mechanically, alfuzosin activated PGK1 directly to stimulate the protein kinase B (AKT) signaling pathway, thus facilitating glucose uptake as well as improving insulin resistance. SignificanceThe present finding has shed a new light on the treatment of DM and provides validation for PGK1 as a therapeutic target for DM.

Induction of Type 2 Diabetes in Mice to Understand Vascular Changes That Drive Diabetic Retinopathy.

Diabetic retinopathy is a common complication of type 2 diabetes. Research into this comorbidity is challenging due to the slow progression of pathological changes and the limited transgenic models available to study disease progression and mechanistic changes. Here, we describe a non-transgenic mouse model of accelerated type 2 diabetes using a high-fat diet in combination with streptozotocin delivered via osmotic mini pump. This model, when subjected to fluorescent gelatin vascular casting, can be used to study vascular changes in type 2 diabetic retinopathy.

Enzymatically-epoxidized docosahexaenoic acid, 19,20-EpDPE, suppresses hepatic crown-like structure formation and nonalcoholic steatohepatitis fibrosis through GPR120

A hepatic crown-like structure (hCLS) formed by macrophages accumulating around lipid droplets and dead cells in the liver is a unique feature of nonalcoholic steatohepatitis (NASH) that triggers progression of liver fibrosis. As hCLS plays a key role in the progression of NASH fibrosis, hCLS formation has emerged as a potential therapeutic target. n-3 polyunsaturated fatty acids (n-3 PUFAs) have potential suppressive effects on NASH fibrosis; however, the mechanisms underlying this effect are poorly understood. Here, we report that n-3 PUFA-enriched Fat-1 transgenic mice are resistant to hCLS formation and liver fibrosis in a NASH model induced by a combination of high-fat diet, CCl4 and a Liver X receptor (LXR) agonist. Liquid chromatography–tandem mass spectrometry-based mediator lipidomics revealed that the amount of endogenous n-3 PUFA-derived metabolites, such as 17,18-dihydroxyeicosatetraenoic acid (17,18-diHETE), and 19,20-epoxy docosapentaenoic acid (19,20-EpDPE), was significantly elevated in Fat-1 mice, along with hCLS formation. In particular, DHA-derived 19,20-EpDPE produced by Cyp4f18 attenuated the hCLS formation and liver fibrosis in a G protein-coupled receptor 120 (GPR120)-dependent manner. These results indicated that 19,20-EpDPE is an endogenous active metabolite that mediates the preventive effect of n-3 PUFAs against NASH fibrosis.

Sex Differences in the Effects of High Fat Diet on Neuroinflammation in a Mouse Model of VCID

AbstractBackgroundNeuroinflammation plays a central role in the progression of vascular contributions to cognitive impairment and dementia (VCID). Unfortunately, anti‐inflammatory therapeutics have proven insufficient so far at ameliorating the progression of VCID. This may be because broadly suppressing inflammation prohibits its beneficial functions. Instead, supporting endogenous inflammation resolving programs may prove more effective. Mid‐life metabolic disease is a major risk factor for VCID, particularly in women. Therefore, we examined neuroinflammation at middle‐age in both males and females with VCID. We modeled metabolic disease via long‐term administration of a high fat (HF) diet, and VCID via unilateral carotid artery occlusion surgery which results in chronic cerebral hypoperfusion. We hypothesized that metabolic disease would lead to more adverse cognitive and neuroinflammatory effects in middle‐aged females compared to males in a mouse model of VCID.Method8.5 month old male and female C57BL/6J mice were placed on a HF or control diet for 7 months. At month 3, they received VCID or sham surgery. At month 6, cognitive function was assessed. Half of the brains were collected for histology while the other half were flash frozen for qPCR analysis of pro‐inflammatory and pro‐resolving mediators.ResultHippocampal‐dependent spatial memory was impaired in VCID males, regardless of diet; however, in females, both HF diet and VCID (or a combination of the two) impaired spatial memory. In males, HF diet increased microglial activity in the hippocampus. Additionally, HF diet in combination with VCID surgery increased expression of pro‐inflammatory markers as well as pro‐resolving mediators in males. However, females on a HF diet experienced a suppression of microglia activity in the hippocampus. HF‐fed females, regardless of surgery, had decreased expression of both pro‐inflammatory markers as well as pro‐resolving mediators.ConclusionIn line with clinical findings, these data suggest that metabolic disease increases cognitive deficits to a greater extent in middle‐aged females than males. Further, our data suggest VCID with metabolic disease increases neuroinflammation and its resolution in males, while metabolic disease suppresses neuroinflammation and its resolution in females. This highlights the need for a better understanding of the sex differences in neuroinflammation following vascular injury.

Abstract 15701: Histone Deacetylase 6Inhibition Demonstrates Comparable Efficacy as Empagliflozin in a Mouse Model of Heart Failure With Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with high morbidity and mortality, yet there are few effective therapies for HFpEF. Previously, we have demonstrated that TN-301, a highly selective small molecule inhibitor of histone deacetylase 6 (HDAC6), works directly on the heart and on systemic metabolism and inflammation in mouse models of HFpEF. Recently, empagliflozin, a selective inhibitor of sodium-glucose transport protein (SGLT2) inhibitor, was approved in the U.S. for patients with HFpEF. Purpose: We aimed to compare the efficacy of HDAC6i and SGLT2i in a mouse model of established diastolic dysfunction with preserved ejection fraction. Methods and Results: To recapitulate systemic and cardiovascular features of HFpEF in humans, we induced diastolic dysfunction with a combination of high fat diet and inhibition of constitutive nitric oxide synthase using N ω -nitrol-arginine methyl ester (L-NAME). After the HFpEF phenotypes were established, mice received TYA-11018 (TN-301-like HDAC6i) or empagliflozin, or vehicle orally once daily for 9 weeks. We found that TYA-11018 reduced left ventricular hypertrophy and restored diastolic function with comparable efficacy to empagliflozin. In addition, TYA-11018 reduced fasting glucose and improved glucose tolerance in HFpEF mice, to levels similar to empagliflozin. Preliminary data suggested TYA-11018 corrects hyperglycemia independently of glucose urine excretion, which is distinct from SGLT2i. Using whole transriptome RNA-seq, TYA-11018 showed greater effects on correcting expression of gene sets associated with inflammation, fibrosis and mitochondrial energy production compared to empagliflozin in HFpEF hearts. Conclusion: Our results show that with its distinct HDAC6 inhibition mechanism, TYA-11018 reverses preexisting hypertrophy, diastolic dysfunction and glucose tolerance, demonstrated similar efficacy to that with a SGLT2 inhibitor in HFpEF model. The comparable efficacy seen in this HFpEF model with TYA-11018 and empagliflozin provides early but encouraging evidence of the potential translatability of these findings to clinical development. We are developing TN-301 for treating HFpEF patients.

High-fat diet combined with dextran sulfate sodium failed to induce a more serious NASH phenotype than high-fat diet alone

Background and Aims: Animal models are essential tools to investigate the pathogenesis of diseases. Disruption in the intestinal epithelial barrier and gut vascular barrier is an early event in the development of non-alcoholic fatty liver disease (NAFLD). Intestinal epithelial barrier can be destroyed by dextran sulfate sodium (DSS) oral administration. High fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH) rat model has been widely used. Recently, the combination of HFD with DSS induced NASH model has also been reported. The present study aimed to evaluate whether this composite NASH animal model is more ideal than that induced by HFD alone. Methods: Rats were divided into control, HFD and HFD combined with DSS (DSS + HFD) groups. They were fed with routine diet, high-fat diet, and HFD combined with DSS drinking, respectively, for 22 weeks. Histopathological analysis (HE staining, Oil-Red O staining, Masson staining), lipid parameters testing (TG, TC, GLU, NEFA, TRIG, LDL, HDL), testing on indicators of inflammation (TNF-α, ALT, AST, ALP, LDH) and oxidative stress (MDA, SOD, CAT) were performed. Results: Rats in HFD and DSS + HFD group displayed increase in the body weight, liver weight, lipids accumulation and the levels of TNF-α, ALT, AST, ALP, MDA in serum and liver accompanied with impaired glucose tolerance, obvious hepatitis, and decreased levels of SOD and CAT in serum and liver compared to those in control group. Moreover, in the DSS + HFD group, but not in the HFD group, proliferation of fibrous tissue in the portal area and the hepatic lobules was found. Conclusion: The addition of DSS on high-fat diet did not exacerbate lipid accumulation and inflammation, but induced NASH-related liver fibrosis.

Combination of high-fat diet and cadmium impairs testicular spermatogenesis in an m6A-YTHDF2-dependent manner

Environmental cadmium (Cd) or high-fat diet (HFD) exposure alone are risk factors of male infertility. However, the effect and mechanism of co-exposure to HFD and Cd on sperm quality remain unclear. This study was aimed to explore the combined effects of HFD and Cd on spermatogenesis as well as its m6A-dependent mechanism in vivo and in vitro. As a result, co-exposure of HFD and Cd resulted in a significant decrease in the number of mature testicular seminiferous tubules and epididymis sperm quantity in mice, compared with Cd or HFD exposure alone. Correspondingly, the mRNAs expression of Smc3(spermatocytes marker), Acrv1(round spermatids marker) and Lzumo3(elongated spermatids marker) were downregulated in HFD and Cd group. Furthermore, combined exposure downregulated the expression of meiosis-related proteins (STRA8 and SYCP3), increased the m6A level of Stra8, and upregulated the expression of m6A-related proteins (METTL3 and YTHDF2) in mouse spermatocytes. Mechanistically, the above-mentioned impacts caused by co-exposure were markedly restored by Mettl3 siR and Ythdf2 siR. In addition, RNA stability assay showed that Ythdf2 siR obviously reversed co-exposure-increased Stra8 mRNA degradation rate in actinomycin-D-treated mouse spermatocytes. Meanwhile, excess ROS was observed in combined-exposure group, and a free radical scavenger N-tert-Butyl-α-phenylnitrone (PBN) attenuated co-exposure-upregulated expression of METTL3 and YTHDF2 in mouse spermatocytes. These results suggested that combination of HFD and Cd impaired spermatogenesis by degrading Stra8 in an m6A-YTHDF2-dependent manner via ROS activation.

Antidiabetic effect of Melicope glabra (Blume) T.G. Hartley (Rutaceae) in high-fat diet/streptozotocin-induced diabetic rats and its bioactive components

Melicope glabra­ (Blume) T. G. Hartley is a plant of Rutaceae family. The present study aimed to evaluate the in vivo hypoglycemic effect of M. glabra leaves extract on diabetic rats and identify its bioactive components. The induction of diabetes in Sprague-Dawley rats was done by a combination of high-fat diet and low-dose streptozotocin injection. The M. glabra extracts and standard sitagliptin were orally administered once daily to the diabetic rats for 28 days. The diabetic rats showed drastic weight loss, hyperglycemia, poor glucose tolerance, hyperlipidemia, and disturbances in the liver and kidney functions. However, oral administration of M. glabra extracts to the diabetic rats significantly lowered the DPP-4 level and increased glucagon-like peptide-1 (GLP-1) level. Scopoletin, pachypodol, and stigmasterol were revealed as the active DPP-4 and α-amylase inhibitors. This study revealed novel findings which suggest the

Anti-oxidative effects of functional food, Lignosus rhinocerus sclerotia (TM02® cultivar) using a type 2 diabetes mellitus rodent model

Lignosus rhinocerus is a highly valued medicinal mushroom traditionally consumed by the indigenous communities of Southeast Asia as treatment for numerous ailments, some of which are linked to its antioxidative activities. While the antioxidative capacity of L. rhinocerus has been established in vitro, lack of translational studies are available on the effect of L. rhinocerus in the pathogenesis of diseases driven by high oxidative stress. This study aims to investigate the in vivo antioxidative effects of cultivated Lignosus rhinocerus (TM02®) sclerotia in a multifaceted in vivo model of oxidative stress, induced by chronic hyperglycemia associated with diabetes. A type 2 diabetes mellitus (T2DM) rodent model was generated using a high-fat diet in combination with low dose streptozotocin after which TM02® cultivar, at a dose of 200 mg/kg, was administered orally for 14 days. Diabetic rats treated with TM02® cultivar had decreased plasma AGEs concentration, complemented with improved mitochondrial respiratory function associated with elevated cardiac and skeletal muscle ATP concentrations in both diabetic and non diabetic rats. Interestingly, TM02® cultivar-treated rats have improved glycemic control, with the potential ability to induce insulin secretion. Our findings revealed that TM02® exhibits antioxidative effects to potentially alleviate diabetes-related complications associated with AGEs accumulation, with significant effects in enhancing mitochondrial function and energy production.

Abstract GS114: Maladaptive Myeloid Lipid Metabolism Promotes Cardiac Diastolic Dysfunction Through Splenic Hematopoiesis

Rationale: Diastolic dysfunction, including during heart failure with preserved ejection fraction (HFpEF), is a widespread morbidity with limited therapeutic options. Though heterogeneous in etiology, major risk factors include hyperlipidemia, hypertension, and elevated inflammation. Inflammatory macrophages have been implicated in the promotion of diastolic dysfunction; however underlying mechanistic insight remains in its infancy. Objective: We set out to define the heterogeneity of the cardiac immune response during diastolic dysfunction to identify cell and molecular protagonists relevant to HFpEF. We hypothesized that systemic metabolic perturbations during HFpEF were promoting cardiac inflammation and fibrosis. Methods and Results: Diastolic dysfunction was induced by a combination of high fat diet (HFD) and iNOS inhibition (L-NAME). scRNAseq of the myocardium revealed significant alterations in the composition of cardiac macrophage subsets. Gene ontology analyses depicted a specific induction of pro-fibrotic and lipid handling pathways, including the fatty acid receptor Cd36. In live animals, myeloid deficiency of Cd36 prevented diastolic dysfunction and was associated with dampened cardiac inflammation. When investigating immune cell sourcing during HFpEF, it was found that a splenic hematopoietic niche formed in wild-type mice. Within splenic macrophages, HFpEF-associated risk factors activated mitochondrial metabolism, as well as expression of vascular cell adhesion molecule-1 (VCAM-1), the latter which has been shown to retain hematopoietic stem cells in the spleen. In vitro treatment of splenic macrophages with high fat was sufficient to induce expression of Vcam1, an effect found to be mediated by mitochondrial reactive oxygen species activation of the transcription factor Spic. Conclusions: Our data suggest a critical role for myeloid metabolism in the sourcing of detrimental-monocyte-derived macrophages from the spleen, to the heart.

Noni (Morinda citrifolia L.) fruit phenolic extract supplementation ameliorates NAFLD by modulating insulin resistance, oxidative stress, inflammation, liver metabolism and gut microbiota

The liver-protective activity of phenolics has been consistently reported, but the underlying protective mechanism of phenolic extract from noni fruit (NFE) against high-fat-diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) remains unclear. Mice were fed with HFD or combination of HFD and NFE for 10 weeks, and then the gut microbiota and liver metabolites were compared. In this study, NFE supplementation alleviated HFD-induced liver injury and metabolic comorbidities, as evidenced by reduced liver function markers, decreased lipid profile levels, and improved obesity and insulin resistance. NFE supplementation restored the composition of gut microbiota with a remarkable elevation in the relative abundance of Parabacteroides, Lactobacillus, Roseburia, Akkermansia and a significant reduction in Helicobacter, norank_f_Desulfovibrionaceae, Desulfovibrio, Mucispirillum at the genus level. Liver metabolomics demonstrated that NFE supplementation favorably regulated the metabolic pathways involved in oxidative stress and inflammation, including purine metabolism, glutathione metabolism, primary bile acid biosynthesis, glycerophospholipid metabolism, pentose phosphate pathway, ascorbate and aldarate metabolism, galactose metabolism etc. Furthermore, NFE supplementation inhibited the HFD-induced activation of the liver endotoxin − TLR4 − NF-κB pathway, and alleviated liver inflammation. In conclusion, the findings of this study provide new evidences supporting that NFE can be used as a therapeutic approach for HFD-induced NAFLD via modulating the gut microbiota composition, liver metabolite profile and suppressing inflammatory reaction.

THE COMBINATION OF HIGH FAT DIET AND MONOSODIUM GLUTAMATE ALTERING ADIPOGENESIS, BRAIN RESISTIN AND SERUM CORTISOL LEVEL IN FEMALE RAT

Home / Archives / Vol. 8 No. 2 (2022): July / Research Article THE COMBINATION OF HIGH FAT DIET AND MONOSODIUM GLUTAMATE ALTERING ADIPOGENESIS, BRAIN RESISTIN AND SERUM CORTISOL LEVEL IN FEMALE RAT Authors Aris Widayati Department of Physiology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia Dewi Mustika Department of Physiology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia Yhusi Karina Riskawati Department of Physiology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia Agustin Iskandar Department of Parasitology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia Nia Kurnianingsih Department of Physiology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia DOI: https://doi.org/10.21776/ub.mnj.2022.008.02.8 Keywords: glutamate, fat diet, inflammation, behavior, BDNF Abstract Background: The prevalence of obesity is increasing tremendously worldwide. Obesity is correlated with the consumption of a high-fat diet (HFD) and monosodium glutamate (MSG). Although the effect of MSG or HFD on inflammation has been established, lack of information about the effects of both combination on simultaneous systemic and brain inflammation that can be evaluated from cortisol serum and brain resistin level respectively. Objectives: This study aimed to investigate the effects of combining HFD and MSG on brain resistin, serum cortisol, lipid profiles, visceral weight, and body weight gain. Methods: Sixteen adult female rats were randomized into 4 groups consist of standard diet; HFD+MSG 0.05 mg/gBW, HFD+MSG 0.2 mg/gBW and HFD+MSG 0.35 mg/gBW. Lipid profiles were measured using automatic biochemical analyzer. Brain resistin and serum cortisol level were determined using enzyme-linked immunoassay. Results: The groups of HFD+MSG significantly have higher level of brain resistin (p<0.003), serum cortisol (p<0.01), total cholesterol (p<0.003) and visceral fat weight (p<0.05) than control group. Conclusion: The combination of HFD, and MSG generates obesity that led to systemic-brain alteration on inflammation. Further study is necessary to evaluate further the functional impact of both combinations on behavioral profiles.

Terminalia catappa aqueous leaf extract reverses insulin resistance, improves glucose transport and activates PI3K/AKT signalling in high fat/streptozotocin-induced diabetic rats

Rising prevalence of type 2 diabetes mellitus (T2DM) in sub-Saharan Africa has necessitated surveys of antidiabetic medicinal plants. This study assessed the antidiabetic mechanism of Terminalia catappa aqueous leaf extract (TCA) in high fat/low dose streptozotocin-induced type 2 diabetic rats. T2DM was induced by a combination of high-fat diet and low dose STZ (30 mg/kg bw) and the animals were administered with TCA (400 and 800 mg/kg bw) orally daily for 28 days. Biochemical parameters and indices for diabetes including renal function tests and pancreatic histology were evaluated. Relative expression of hepatic insulin resistance, signalling and glucose transport genes were also assessed. Induction of T2DM resulted in significant (p < 0.05) weight loss, dysregulated glucose level and clearance, electrolyte imbalance and disrupted diabetic biochemical parameters. Diabetes onset also perturbed β-cell function and insulin resistance indices, damaged pancreas microanatomy, while disrupting the expression of insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and glucose transporter isoform 4 (GLUT-4) mRNA. Oral treatment of diabetic animals with TCA significantly (p < 0.05) ameliorated alterations due to T2DM induction in a manner comparable with glibenclamide. These results suggest TCA exerts its antidiabetic action by reversing insulin resistance, improving glucose transport and activating PI3K/AKT signalling.

Protective effects of L-arginine on cognitive deficits and biochemical parameters in an experimental model of type-2 diabetes mellitus induced Alzheimer's disease in rats.

Alzheimer's disease (AD) has been closely linked to type 2 diabetes mellitus (T2DM) and insulin resistance plays a key role in the onset and development of AD. It has also been reported that NO donors play an important role in diabetes and have neuroprotective activity. The present study evaluated the effects NOS substrate, L-arginine and NOS-blocker, NG-nitro-L-arginine methyl ester (L-NAME) on cognitive functions, brain amyloid β levels and other associated biochemical markers in diabetes (T2DM)-induced AD in rats. T2DM was induced by a combination of high fat diet (HFD) and streptozotocin (STZ) (35 mg/kg, i.p.). Pretreatment with L-arginine (100 mg/kg/day) improved diabetes related biochemical parameters viz. plasma glucose, triglycerides and cholesterol. In addition, L-arginine also improved insulin levels and glucose tolerance. On the other hand, NO synthase inhibitor, L-NAME (10 mg/kg), did not have much influence on these parameters. Further, L-arginine treatment showed ameliorative effects on cognitive deficits seen in the Morris water maze (MWM) test when compared to the vehicle (saline) treated group and similar results were observed in the passive avoidance test. These neurobehavioural changes were associated with predictable modulations in Aβ levels in hippocampus and cortex in HFD + STZ + saline group, which were attenuated in the L-arginine, but not in the L-NAME-treated group. Our results indicate that L-arginine could be a considered a potential therapeutic strategy to attenuate the diabetes induced cognitive deficits in AD.

Comparative effect of vitamin D3 and carbenoxolone treatments in metabolic syndrome rats.

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including central obesity, hypertension, insulin resistance, dyslipidemia, and hyperglyemia. MetS is found to be a positive predictor of cardiovascular morbidity and mortality. The present study was planned to test the efficacy of vitamin D3 supplementation as compared with cortisol inhibition on MetS parameters. Wistar rats were allocated into four groups: control, untreated MetS, and MetS treated with either vitamin D3 (10 µg/kg) or carbenoxolone (50 mg/kg). MetS was induced by combination of high-fat diet and oral fructose. After the induction period (8 weeks), MetS was confirmed, and treatment modalities started for a further 4 weeks. Compared with untreated MetS, vitamin D3- and carbenoxolone-treated rats showed significant reduction in blood pressure, body mass index, Lee index, waist circumference, retroperitoneal fat, and improvement of dyslipidemia. Meanwhile, treatment with carbenoxolone significantly lowered the elevated liver enzymes, and vitamin D3 resulted in improved insulin sensitivity, enhanced glucose uptake by muscles, and replenished glycogen content in the liver and muscles near control levels. In conclusion, although treatment with vitamin D3 or carbenoxolone reduced the risk factors associated with MetS, vitamin D3 was effective in ameliorating insulin resistance which is the hallmark of MetS.

Silencing of FOS-like antigen 1 represses restenosis via the ERK/AP-1 pathway in type 2 diabetic mice.

Restenosis is a major limiting factor for a successful outcome in type 2 diabetes (T2D) patients undergoing percutaneous coronary intervention (PCI). The aim of this study is to explore the role and regulatory mechanism of FOS-like antigen 1 (FOSL1) in restenosis in T2D. A T2D with restenosis mouse model was established by the combination of high-fat diet and streptozotocin injection and by wire-injury. High glucose (HG)-treated vascular smooth muscle cells (VSMCs) were used to mimic T2D in vitro. The results of quantitative real time PCR and western blotting demonstrated that the expression of FOSL1 was increased not only in T2D mice or HG-induced VSMCs, but also in T2D mice that underwent wire-injury. HE staining revealed that FOSL1 knockdown significantly reduced the intimal/media ratio of T2D mice after wire-injury. Silencing of FOSL1 reversed the promoting effects of HG treatment on viability, migration and inflammation reactions, and the inhibiting effect on the apoptosis of VSMCs. Inhibition of ERK/AP-1 pathway obtained similar patterns in HG-induced VSMCs. The activation of ERK/AP-1 pathway reversed the influence of FOSL1 knockdown on HG-induced VSMCs. Our findings indicate that silencing of FOSL1 may suppress restenosis via regulation of the ERK/AP-1 pathway in T2D mice, pointing out a potential therapeutic target to prevent restenosis in T2D.

A new mouse model of type 2 diabetes mellitus established through combination of high-fat diet, streptozotocin and glucocorticoid

AimA stable induced type 2 diabetes model (T2DM) still needs to be explored for basic and clinical research, due to nonuniform model methods and unstable consequences. Our aims were to explore and establish an optimized induced T2DM model in mice that exhibits insulin resistance and β-cell damage. Materials and methodsC57BL/6 mice were treated with a high-fat diet (HFD), streptozotocin (STZ) and dexamethasone (DEX) at different doses and in combination. The general growth status, blood glucose and fasting insulin were detected, and the success rate and insulin sensitivity indices were calculated. Key findingLow-dose STZ injection multiple times was more secure in the process of T2DM model production. Combined intervention was more efficient in reducing insulin sensitivity and improving the success rate of T2DM model construction. SignificanceCombined with a high-fat diet, glucocorticoids and streptozotocin, a new mouse model of T2DM with insulin resistance and β-cell damage could be established. The optimized experimental method can serve as a stable model for further studies on the mechanisms and therapy of T2DM.

Food for Thought: Consumption of a High-Fat Diet in Combination With Antibiotics Results in Early Inflammatory Changes in the Gastrointestinal Tract

Food for Thought: Consumption of a High-Fat Diet in Combination With Antibiotics Results in Early Inflammatory Changes in the Gastrointestinal Tract

Exposure to cigarette smoke precipitates simple hepatosteatosis to NASH in high-fat diet fed mice by inducing oxidative stress.

Consumption of diet rich in fat and cigarette smoking (CS) are independent risk factors of non-alcoholic steatohepatitis (NASH), and they often occur together in some populations. The present study investigated the mechanisms of high-fat diet (HFD) and CS, individually and in combination, on the pathogenesis of NASH in mice. C57BL/6 male mice were subjected to either a low-fat chow (CH) or HFD with or without mainstream CS-exposure (4 cigarettes/day, 5 days/ week for 14 weeks). HFD alone caused hepatosteatosis (2.5-fold increase in TG content) and a significant increase in 3-nitrotyrisine (by ∼40-fold) but without an indication of liver injury, inflammation or fibrosis. CS alone in CH-fed mice increased in Tnfα expression and macrophage infiltration by 2-fold and relatively less increase in 3-nitrotyrosine (18-fold). Combination of HFD and CS precipitated hepatosteatosis to NASH reflected by exacerbated makers of liver inflammation and fibrosis which were associated with much severe liver oxidative stress (90-fold increase in 3-nitrotyrisine along with 6-fold increase in carbonylated proteins and 56% increase in lipid oxidations). Further studies were performed to administer the antioxidant tempol to CS exposed HFD mice and the results showed that the inhibition of liver oxidative stress prevented inflammatory and fibrotic changes in liver despite persisting hepatosteatosis. Our findings suggest that oxidative stress is a key mechanism underlying CS-promoted progression of simple hepatosteatosis to NASH. Targeting hepatic oxidative stress may be a viable strategy in halting the progression of metabolic associated fatty liver disease.