Diet-induced Model Research Articles

High-fat, high-carbohydrate diet-induced experimental model of metabolic syndrome in rats

Purpose. The study is focused on development of high-fat, high-carbohydrate diet-induced experimental model of metabolic syndrome (MS) in rats. Materials and methods. The 6-week old Wistar rats ( n = 20) were used for study. Rats were separated into control and experimental groups. The rats from the control group were fed standard rat chow. The rats from the experimental group had a high-fat, high-carbohydrate diet rich in lard (17%) and fructose (17%) and drank 20% fructose solution. At the end of the study, body weight and blood pressure (BP) were assessed. After 12 weeks of a diet load, an oral glucose tolerance test (GTT) and insulin tolerance test (ITT) were carried out. Lipid and protein biochemical parameters in plasma were analyzed. Adipose tissue and liver were measured at the end of the study. The levels of triacylglycerol (TAG) and cholesterol (Сh) in the liver were determined by enzymatic methods. Results. High-fat, high-carbohydrate diet feeding in rats for 12 weeks led to BP elevation and increase in the adipose tissue/body weight ratio. Hyperglycemia, impaired glucose tolerance and insulin resistance were found in rats with MS by means of GTT and ITT. Elevation of plasma TAG level was observed in the experimental group, although plasma total Сh and HDL-Ch did not differ from those of controls. Liver/body weight ratio and the level of TAG and Ch in the liver were elevated in rats with MS. Conclusion. Experimental rat model of diet-induced MS reproduces many aspects of MS in humans. This model may be useful for studying the pathophysiology of MS and methods for its prevention and treatment.

Hypothalamic gene transfer of BDNF promotes healthy aging.

The aging process and age-related diseases all involve metabolic decline and impaired ability to cope with adversity. Environmental enrichment (EE)-a housing environment which recapitulates aspects of active lifestyle-exerts a wide range of health benefits in laboratory rodents. Brain-derived neurotrophic factor (BDNF) in the hypothalamus orchestrates autonomic and neuroendocrine processes, serving as one key brain mediator of EE-induced resistance to obesity, cancer, and autoimmunity. Recombinant adeno-associated virus (AAV)-mediated hypothalamic BDNF gene transfer alleviates obesity, diabetes, and metabolic syndromes in both diet-induced and genetic models. One recent study by our lab demonstrates the efficacy and safety of a built-in autoregulatory system to control transgene BDNF expression, mimicking the body's natural feedback systems in middle-age mice. Twelve-month old mice were treated with autoregulatory BDNF vector and monitored for 7months. BDNF gene transfer prevented age-associated metabolic decline by: reducing adiposity, preventing the decline of brown fat activity, increasing adiponectin while reducing leptin and insulin in circulation, improving glucose tolerance, increasing energy expenditure, alleviating hepatic steatosis, and suppressing inflammatory genes in the hypothalamus and adipose tissues. Furthermore, BDNF treatment reduced anxiety-like and depression-like behaviors. This chapter summarizes this work and discusses potential roles that hypothalamic BDNF might play in promoting healthy aging.

The role of pioglitazone in antioxidant, anti-inflammatory, and insulin sensitivity in a high fat-carbohydrate diet-induced rat model of insulin resistance.

We explored the cascade effects of a high fat-carbohydrate diet (HFCD) and pioglitazone (an anti-diabetic therapy used to treat type 2 diabetes mellitus (T2DM)) on lipid profiles, oxidative stress/antioxidant, insulin, and inflammatory biomarkers in a rat model of insulin resistance. Sixty albino rats (80-90 g) were randomly divided into three dietary groups; 1) standard diet; 2) HFCD diet for 12 weeks to induce an in vivo model of insulin resistance; and 3) HFCD diet plus pioglitazone. Blood and tissue samples were taken to assess hepatic function, lipid profiles, oxidative biomarkers, malondialdehyde (MDA) levels, antioxidant defense biomarkers, including reduced glutathione (GSH), superoxide dismutase (SOD), and the inflammatory markers interleukin-6 (IL-6) and tumor necrotic factor (TNF-α). HFCD-fed rats had significantly (P≤0.05) increased serum triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein (LDL), alanine transaminase (ALT), and bilirubin levels, but decreased high-density lipoprotein (HDL) levels compared with the normal group. Moreover, serum leptin, resistin, TNF-α, and IL-6 levels were increased significantly in HFCD animals compared with controls. Similarly, HFCD-induced insulin resistance caused antioxidant and cytokine disturbances, which are important therapy targets for pioglitazone. Importantly, administration of this drug ameliorated these changes, normalized leptin and resistin and inflammatory markers by reducing TNF-α levels. Metabolic cascades of elevated lipid profiles, oxidative stress, insulin, and inflammatory biomarkers are implicated in insulin resistance progression. HFCD induced metabolic cascades comprising hypertriglyceridemia, hyperglycemia, insulin resistance, obesity-associated hormones, and inflammatory biomarkers may be alleviated using pioglitazone.

Lipotoxic hepatocytes promote nonalcoholic fatty liver disease progression by delivering microRNA-9-5p and activating macrophages.

M1-polarized macrophages are involved in chronic inflammatory diseases, including nonalcoholic fatty liver disease (NAFLD). However, the mechanisms responsible for the activation of macrophages in NAFLD have not been fully elucidated. This study aimed at investigating the physiological mechanisms by which extracellular vesicles (EVs)-encapsulated microRNA-9-5p (miR-9-5p) derived from lipotoxic hepatocytes might activate macrophages in NALFD. After blood sample and cell collection, EVs were isolated and identified followed by co-culture with macrophages. Next, the palmitic acid-induced cell and high fat diet-induced mouse NALFD models were established to explore the in vitro and in vivo effects of EVs-loaded miR-9-5p on NAFLD as evidenced by inflammatory cell infiltration and inflammatory reactions in macrophages. Additionally, the targeting relationship between miR-9-5p and transglutaminase 2 (TGM2) was identified using dual-luciferase reporter gene assay. miR-9-5p was upregulated in the NAFLD-EVs, which promoted M1 polarization of THP-1 macrophages. Furthermore, miR-9-5p could target TGM2 to inhibit its expression. Downregulated miR-9-5p in NAFLD-EVs alleviated macrophage inflammation and M1 polarization as evidenced by reduced levels of macrophage inflammatory factors, positive rates of CD86+ CD11b+, and levels of macrophage surface markers in vitro. Moreover, the effect of silencing of miR-9-5p was replicated in vivo, supported by reductions in TG, TC, AST and ALT levels and attenuated pathological changes. Collectively, lipotoxic hepatocytes-derived EVs-loaded miR-9-5p downregulated the expression of TGM2 and facilitated M1 polarization of macrophages, thereby promoting the progression of NAFLD. This highlights a potential therapeutic target for treating NAFLD.

Hyperglycemia compromises the ischemia-provoked dedifferentiation of cerebral pericytes through p21-SOX2 signaling in high-fat diet-induced murine model.

Aim:Diabetes-related cerebral small vessel disease (CSVD) causes neurological deficits. Patients with diabetes showed pericyte loss as a hallmark of retinopathy. Cerebral pericytes, which densely localize around brain capillaries, are quiescent stem cells regulating regeneration of brain and may have a role in CSVD development. This study investigated whether diabetes impairs ischemia-provoked dedifferentiation of pericytes.Methods:A murine high-fat diet (HFD)-induced diabetes model was used. After cerebral ischemia induction in the mice, pericytes were isolated and grown for a sphere formation assay.Results:The sphere counts from the HFD group were lower than those in the chow group. As the spheres formed, pericyte marker levels decreased and SOX2 levels increased gradually in the chow group, but not in the HFD group. Before sphere formation, pericytes from the HFD group showed high p21 levels. The use of a p21 inhibitor rescued the reduction of sphere counts in the HFD group. At cellular level, hyperglycemia-induced ROS increased the level of p21 in cerebral pericytes. The p21-SOX2 signaling was then activated after oxygen-glucose deprivation.Conclusion:HFD-induced diabetes compromises the stemness of cerebral pericytes by altering p21–SOX2 signaling. These results provide evidence supporting the role of pericytes in diabetes-related CSVD and subsequent cerebral dysfunction.

Centella Asiatica Effect in A High Fat and Fructose Diet-Induced Model of Metabolic Disorder in Rats

Centella Asiatica Effect in A High Fat and Fructose Diet-Induced Model of Metabolic Disorder in Rats

Identification of disease-associated microRNA in a diet-induced model of nonalcoholic steatohepatitis.

Emerging evidence suggests that microRNA dysregulation plays an important role in nonalcoholic steatohepatitis. Using a model of diet-induced liver disease that progresses to fibrosis and hepatocellular carcinoma, we identify a set of 22 microRNA with robust correlation with liver enzyme levels and liver collagen content. These disease-asssociated miRs play pivotal roles in steatosis, extracellular matrix deposition and liver cancer, and may form the basis for identification of therapeutic strategies against this form of liver disease.

Effect of antihyperlipidemic polyherbal formulation in high diet induced hyperlipidemia wistar albino rats. An in vitro - in vivo evaluation

Hyperlipidemia is a prevalent global health problem, and it is linked to various cardiovascular disorders. The side effects of the current lipid-lowering drugs have increased the tendency to move toward traditional and alternative remedies. The study aims to Formulate and evaluate the Antilipidemic activity of Polyherbal formulations used as a traditional medicine in the Malabar area, Kerala by in vitro and in vivo methods. Further, the present study also compares the impact of seasonal variations on chemical contents of ingredient herbs of polyherbal medicine. They were analyzed for, anti-oxidant activity by DPPH and Nitric oxide method and In-vitro anti-cholesterol activity by cholesterol enzymatic endpoint method using simavastatin as a positive control. The formulation showing highest anti-oxidant and in- vitro Antilipidemic activity was selected for in-vivo analysis. Out of four formulations, PHF 1 shows low IC50 values in DPPH and Nitric oxide methods (250.45± 0.60, 985.40±5.59), respectively. The in-vitro anti-cholesterol activity showed a maximum % of inhibition for PHF1. Based on this PHF 1was selected for in vivo analysis. Acute toxicity was performed according to OECD guidelines. The antilipidemic activity was conducted by Diet-induced hyperlipidemia model in Wistar albino rats, containing six animals in each group. All the groups except saline control received a high-fat diet for two weeks. The Polyherbal formulation (200 mg/kg & 400 mg/kg) showed significant (P<0.05) reduction in total serum cholesterol and lipid levels compared to the vehicle control group. This present study proved that Polyherbal formulation has Antilipidemic activity against the diet-induced hyperlipidemia model by reducing the total serum cholesterol (TC), triglycerides (TG), very low-density lipid (VLDL), low-density lipids(LDL) levels and increasing high-density lipid (HDL) level.

Improvement of Hypertriglyceridemia by Roasted Nelumbinis folium in High Fat/High Cholesterol Diet Rat Model.

Hypertriglyceridemia is a condition characterized by high triglyceride levels and is a major risk factor for the development of cardiovascular diseases. The present study was designed to investigate the inhibitory effect of roasted Nelumbinis folium (RN), which is a medicinal substance produced by heating lotus leaves, on lipid metabolism in high fat/cholesterol (HFC) diet-induced hypertriglyceridemia. Except for those in the control group, Sprague–Dawley rats were fed an HFC diet for four weeks to induce hypertriglyceridemia. During the next nine weeks, the control, regular diet; HFC, HFC diet, FLU, fluvastatin (3 mg/kg/day); RNL, RN (100 mg/kg/day); RNH, RN (200 mg/kg/day) were orally administered together with the diet, and the experiments were conducted for a total of 13 weeks. The weight of the epididymal adipose tissue, liver, and heart of rats in the HFC diet group significantly increased compared to those in the control group but improved in the RN-treated group. It was also confirmed that vascular function, which is damaged by an HFC diet, was improved after RN treatment. The levels of insulin, glucose, triglycerides, total cholesterol, and low-density lipoprotein increased in the HFC diet group compared to those in the control group, while the administration of RN attenuated these parameters. In addition, the administration of RN significantly reduced the gene expression of both LXR and SREBP-1, which indicated the inhibitory effect of the biosynthesis of triglycerides caused by RN. The results indicated that RN administration resulted in an improvement in the overall lipid metabolism and a decrease in the concentration of triglycerides in the HFC diet-induced rat model of hypertriglyceridemia. Therefore, our findings suggest that the RN can be a candidate material to provide a new direction for treating hypertriglyceridemia.

Tinospora cordifolia ameliorates brain functions impairments associated with high fat diet induced obesity

Obesity is a rapidly growing health problem worldwide and its prevalence has increased markedly in both the developing and developed nations. It is associated with a range of co-morbidities such as cardiovascular disease, type 2 diabetes mellitus, and cognitive dysfunctions. Therefore, the need for a safe and effective treatment has led to the exploration of natural products for the management of obesity. In the present study, we tested the anxiolytic, anti-apoptotic, and anti-neuroinflammatory potential of Tinospora cordifolia in a high fat diet-induced obesity rat model system. Young female Wistar albino rats were divided into three groups: (1) Low fat diet (LFD), fed on normal chow feed; (2) High fat diet (HFD), fed on diet containing 30% fat by weight; and (3) High fat diet containing extract (HFDE), fed on high fat diet supplemented with the stem powder of T. cordifolia (TCP). The rats from each group were kept on their respective feeding regimen for 12 weeks. The body weight and calorie intake were recorded weekly. The elevated plus maze test and rotarod performance test were performed to evaluate the anxiety-like behavior and locomotor coordination, respectively. The levels of serum cytokines (IL-6 and TNF-α) were estimated and various markers for inflammation, synaptic plasticity, apoptosis, and energy homeostasis were studied by western blotting. The HFDE rats showed reduced anxiety-like behavior and improved locomotor behavior as compared to HFD-induced obese rats. The TCP supplementation in high fat diet suppressed the expression of inflammatory molecules, including serum cytokines (IL-6 and TNF-α), and modulated apoptosis and synaptic plasticity. TCP was found to be effective in managing body weight in HFD-fed rats by maintaining energy metabolism and cellular homeostasis. T. cordifolia may be recommended as a potential therapeutic agent to prevent the adverse effects of obesity and obesity-associated brain dysfunctions.

Acute Elevated Resistin Exacerbates Mitochondrial Damage and Aggravates Liver Steatosis Through AMPK/PGC-1α Signaling Pathway in Male NAFLD Mice.

Resistin was identified as a link between obesity and insulin resistance and is associated with many diseases in mice. Deciphering the related development and molecular mechanism is necessary for the treatment of these diseases. Previous studies have revealed that increased resistin levels are correlated with lipid accumulation and play a role in non-alcoholic fatty liver disease (NAFLD) development. However, the exact mechanisms underlying these processes remain unclear. To further clarify whether acute elevated resistin level exacerbated liver steatosis, a high-fat diet-induced NAFLD animal model was used and treated with or without resistin for 6 days. We discovered that resistin altered mitochondrial morphology, decreased mitochondrial content, and increased lipid accumulation in HFD mice. qRT-PCR and western blot analysis showed that acute elevated resistin significantly altered the gene expression of mitochondrial biogenesis and liver lipid metabolism molecules in HFD mice. Consequently, in vitro experiments verified that resistin reduced the mitochondrial content, impaired the mitochondrial function and increased the lipid accumulation of palmitate-treated HepG2 cells. Additionally, we demonstrated that resistin upregulated proinflammatory factors, which confirmed that resistin promoted the development of inflammation in NAFLD mice and palmitate-treated HepG2 cells. Signaling-transduction analysis demonstrated that acute elevated resistin aggravated liver steatosis through AMPK/PGC-1α pathway in male mice. This reveals a novel pathway through which lipogenesis is induced by resistin and suggests that maintaining mitochondrial homeostasis may be key to treatments for preventing resistin-induced NAFLD aggravation.

Myrrh essential oil-based nanolipid formulation for enhancement of the antihyperlipidemic effect of atorvastatin

Obesity is a growing health problem and a significant contributor to the global burden of disease. Statins have shown efficacy in modulating the mortality risk associated with obesity. Myrrh has recently been proven to reduce body weight gain and improve lipid profiles in obese hyperlipidemic rats. The aim of this study was to formulate and evaluate the anti-obesity potential of a myrrh oil-based nanoemulsion containing the hypolipidemic agent, atorvastatin. A two-factor, three-level, full factorial design was adopted to formulate and optimize the nanoemulsion formulations. The prepared formulations were characterized in terms of drug-excipient compatibility studies, physical appearance, rheological behavior, in vitro drug release, stability, and in vivo anti-obesity potential. The prepared nanoemulsion formulations showed a uniform size distribution with a droplet size within the nano-size range. The release of drug from the nanoemulsion formulations was dependent on the surfactant concentration used. Interestingly, all developed nanoemulsions were stable for up to 3 months upon storage at refrigerator and room temperature. Most importantly, in the high-fat diet-induced obesity rat model, addition of myrrh oil to oleic acid as an oily phase for nanoemulsion showed a synergistic effect to the anti-obesity potential of the hypolipidemic drug atorvastatin. In conclusion, formulating atorvastatin into a myrrh oil-based nanoemulsion might represent a promising approach for augmenting the anti-obesity action of atorvastatin, not only by enhancing its systemic bioavailability, but also by gaining the benefit of the synergistic anti-obesity effect of myrrh oil.

Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments.

Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia. NASH patients with significant fibrosis have increased risk of developing cirrhosis and liver failure. Currently, NASH is the second leading cause for liver transplant in the United States. More importantly, the risk of developing hepatocellular carcinoma from NASH has also been highlighted in recent studies. Patients may have NAFLD for years before progressing into NASH. Although the pathogenesis of NASH is not completely understood, the current “multiple-hits” hypothesis suggests that in addition to fat accumulation, elevated oxidative and ER stress may also drive liver inflammation and fibrosis. The development of clinically relevant animal models and pharmacological treatments for NASH have been hampered by the limited understanding of the disease mechanism and a lack of sensitive, non-invasive diagnostic tools. Currently, most pre-clinical animal models are divided into three main groups which includes: genetic models, diet-induced, and toxin + diet-induced animal models. Although dietary models mimic the natural course of NASH in humans, the models often only induce mild liver injury. Many genetic and toxin + diet-induced models rapidly induce the development of metabolic disruption and serious liver injury, but not without their own shortcomings. This review provides an overview of the “multiple-hits” hypothesis and an evaluation of the currently existing animal models of NASH. This review also provides an update on the available interventions for managing NASH as well as pharmacological agents that are currently undergoing clinical trials for the treatment of NASH.

Effects of bempedoic acid on diet-induced hepatic steatosis in female rats

Background and Aims: Bempedoic acid (BemA), an ATP-citrate lyase (ACLY) inhibitor, reduces cholesterol and fatty acid synthesis. We explored BemA effects in the early stage of non-alcoholic fatty liver disease in a diet-induced rat model of hepatic steatosis.

Effects of kramizole on the expression of apo A-I, APOC2, and SR-B1 genes in the hypercholesterol diet-induced rat model

Background and Aims: Prevention and treatment of atherosclerosis requires early new and safe drugs among aromatic heterocyclic compounds still represents an important biomedical task. In our investigation we used hypercholesterol model of dyslipidemia on rats to analyze the effect of kramizole injection on the expression of the antiatherogenic protein genes: for apo A-I, Apoc2, and scarb1.

High Fat Rodent Models of Type 2 Diabetes: From Rodent to Human.

Poor dietary habits contribute to increased incidences of obesity and related co-morbidities, such as type 2 diabetes (T2D). The biological, genetic, and pathological implications of T2D, are commonly investigated using animal models induced by a dietary intervention. In spite of significant research contributions, animal models have limitations regarding the translation to human pathology, which leads to questioning their clinical relevance. Important considerations include diet-specific effects on whole organism energy balance and glucose and insulin homeostasis, as well as tissue-specific changes in insulin and glucose tolerance. This review will examine the T2D-like phenotype in rodents resulting from common diet-induced models and their relevance to the human disease state. Emphasis will be placed on the disparity in percentages and type of dietary fat, the duration of intervention, and whole organism and tissue-specific changes in rodents. An evaluation of these models will help to identify a diet-induced rodent model with the greatest clinical relevance to the human T2D pathology. We propose that a 45% high-fat diet composed of approximately one-third saturated fats and two-thirds unsaturated fats may provide a diet composition that aligns closely to average Western diet macronutrient composition, and induces metabolic alterations mirrored by clinical populations.

Abstract 14197: C14a Mutation Abolishes Mg53-Aggravated Glucose Metabolic Dysfunction and Exerts a Dominant Therapeutic Target for Ischemia and Reperfusion (i/r) Injury in Diabetic Heart

Introduction: MG53, essential for cardiac ischemic protection, negatively regulates insulin receptor (IR) to trigger globular metabolic dysfunction, which makes up a big obstacle for its clinical use. In vitro evidence shows that C14A site of MG53 might be a promising target both to abolish MG53 regulation on IR and to keep as much protective function. However, in vivo effect on C14A mutation of MG53 is urgent to be explored. Results: Here, we found C14A knock-in mice exerted relieved insulin resistance, blood glucose, and metabolic phenotype in high fat diet-induced pre-diabetic model. C14A mutation did NOT lessen the protective effect of MG53 by either intracellular knock-in or extracellular addition of mutant protein against ischemia/reperfusion(I/R) injury in db/+ mice. Consistent with our previous study, we found that administration of MG53 on diabetic mice showed aggravated blood glucose, insulin resistance, and unstable cardiac function to induce a higher risk under I/R attack. C14A mutation reduced the affinity between IR ECD and MG53 to block recombinant human (rh) MG53-WT-triggered acute hyperglycemia, increased heart infarct area and death rate on db/db mice during I/R injury. Post-conditioning of rhMG53-C14A stabilized intra-operative blood glucose and showed stronger anti-I/R ability than MG53-WT protein on db/db mice. Conclusions: C14A mutation is a potential target for MG53 treatment on diabetic heart. This potential therapeutic approach for the treatment of patients within type 2 diabetes provides a strategy of gene engineering optimizing well-known target to draw on advantages and avoid pitfalls.

Abstract 13091: Pemafibrate Reduced Hepatic Fibrosis and Cardiac Inflammation in Cholesterol-dominant, Atherogenic-Diet Induced Steatohepatitis Model in Mice

Introduction: Pemafibrate reduces serum triglycerides level and has been reported that it also decreased hepatic triglycerides. In recent decades, the number of patients with nonalcoholic fatty liver diseases has increased and it has become a problem that the patients with steatohepatitis would develop cardiovascular diseases. Aim: The aim of this study is to analyze the effect of pemafibrate on hepatic inflammation and cardiac function in a diet-induced steatohepatitis model. Methods: C57Bl/6 wild mice were administered cholesterol-loading atherogenic-diet (Cont group) or the one with pemafibrate 0.1 mg/kg (Pema group) for 3 or 8 weeks, respectively. Serum lipids, hepatic inflammatory cytokines, histology, gene expression, lipid contents, and cardiac magnetic resonance imaging (MRI) were investigated. Left ventricular strain was analyzed by workstation of ENTORRES©. Results: In Pema group, serum HDL-C level was increased, non-HDL-C level was decreased. serum TNFα was decreased (82.0±10.8 v.s. 48.0±2.1, p<0.0001). In liver, gene expression of TNFa, Il1b, Il6, Tgfb, Col1a, Col2a showed marked reduction. In HE staining, destruction of the hepatic lobule structure was improved. F4/80 staining demonstrated marked reduction of macrophage infiltration. In Tunel staining, apoptosis cell was suppressed. Liver lipid extraction study showed total cholesterol and free cholesterol were decreased by 50%. MRI scanning demonstrated that heterogeneous attenuation of longitudinal strain of left ventricular (Figure). Conclusion: Pemafibrate suppresses liver inflammation and inhibit left ventricular dysfunction caused by cholesterol-rich-atherogenic diet.

Modulation of the Gut Microbiome and Obesity Biomarkers by Lactobacillus Plantarum KC28 in a Diet-Induced Obesity Murine Model.

Lactobacillus plantarum KC28 showed a beneficial (anti-obesity) effect in a diet-induced obese (DIO) C57BL/6 murine model receiving an intermediate high-fat diet (IF). This diet was selected for probiotic studies by prior comparisons of different combinations of basic (carbohydrate, protein and fat) components for optimized induction of dietary obesity in a murine model. Prior selection of Lact. plantarum strain KC28 was based on different physiological tests for safety and functionality including cell line adhesion and anti-adipogenic activity. The strain was administered at 5.0×109CFU/mouse/day to the DIO mice (control mice received a normal diet). The anti-obesity effect of KC28 and the well-known probiotic strains Lact. rhamnosus GG (LGG) and Lact. plantarum 299v was assessed over 12weeks. Xenical served as anti-obesity control. The high-fat diet groups receiving strains KC28 and LGG and the control Xenical group showed significant weight loss and notable changes in some obesity-related biomarkers in the liver (significant up-regulation of PGC1-α and CPT1-α only by KC28; p<0.05) and mesenteric adipose tissue (significant down-regulation of ACOX-1, PPAR-γ, and FAS; KC28 p<0.001 for PPAR-γ and FAS), compared with the IF control. Favourable changes in the studied biomarkers suggest a similar beneficial influence of Lact. plantarum KC28 on the alleviation of obesity comparable with that of the two well-studied probiotic strains, LGG and 299v. This probably resulted from a modulation in the cecal microbiota of the IF group by either probiotic strain, yet in a different manner, showing a highly significant increase in the families Desulfovibrionaceae and Lactobacillaceae only in the group receiving Lact. plantarum KC28.

PPAR\u03b1 agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat

We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient l-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis.