Similar changes in muscle lipid metabolism are induced by chronic high‐fructose feeding and high‐fat feeding in C57BL/J6 mice

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Andrographolide mitigates cardiac apoptosis to provide cardio‐protection in high‐fat‐diet‐induced obese mice

Excessive intake of high fat diet (HFD) and associated obese conditions are critical contributors of cardiac diseases. In this study, an active metabolite andrographolide from Andrographis paniculata was found to ameliorate HFD‐induced cardiac apoptosis. C57/BL6 mouse were grouped as control (n = 9), obese (n = 8), low dose (25 mg/kg/d) andrographolide treatment (n = 9), and high dose (50 mg/kg/d) andrographolide treatment (n = 9). The control group was provided with standard laboratory chow and the other groups were fed with HFD. Andrographolide was administered through oral gavage for 1 week. Histopathological analysis showed increase in apoptotic nuclei and considerable cardiac‐damages in the obese group signifying cardiac remodeling effects. Further, Western blot results showed increase in pro‐apoptotic proteins and decrease in the proteins of IGF‐1R‐survival signaling. However, feeding of andrographolide significantly reduced the cardiac effects of HFD. The results strongly suggest that andrographolide supplementation can be used for prevention and treatment of cardiovascular disease in obese patients.     

Alpha-lipoic acid attenuates insulin resistance and improves glucose metabolism in high fat diet-fed mice

Aim:

To investigate whether alpha-lipoic acid (ALA) could attenuate the insulin resistance and metabolic disorders in high fat diet-fed mice.

Methods:

Male mice were fed a high fat diet (HFD) plus ALA (100 and 200 mg·kg⁻¹·d⁻¹) or HFD plus a positive control drug metformin (300 mg·kg⁻¹·d⁻¹) for 24 weeks. During the treatments, the relevant physiological and metabolic parameters of the mice were measured. After the mice were euthanized, blood samples and livers were collected. The expression of proteins and genes related to glucose metabolism in livers were analyzed by immunoblotting and real time-PCR.

Results:

HFD induced non-alcoholic fatty liver disease (NAFLD) and abnormal physiological and metabolic parameters in the mice, which were dose-dependently attenuated by ALA. ALA also significantly reduced HFD-induced hyperglycemia and insulin resistance in HFD-fed mice. Furthermore, ALA significantly upregulated the glycolytic enzymes GCK, HK-1 and PK, and the glycogen synthesis enzyme GS, and downregulated the gluconeogenic enzymes PEPCK and G6Pase, thus decreased glucose production, and promoted glycogen synthesis and glucose utilization in livers. Moreover, ALA markedly increased PKB/Akt and GSK3β phosphorylation, and nuclear carbohydrate response element binding protein (ChREBP) expression in livers. Metformin produced similar effects as ALA in HFD-fed mice.

Conclusion:

ALA is able to sustain glucose homeostasis and prevent the development of NAFLD in HFD-fed mice.     

Changes in hepatic lipogenic and oxidative enzymes and glucose homeostasis induced by an acetyl‐l‐carnitine and nicotinamide treatment in dyslipidaemic insulin‐resistant rats

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C1q/TNF‐related protein 9 improves the anti‐contractile effects of perivascular adipose tissue via the AMPK‐eNOS pathway in diet‐induced obese mice

The anti‐contractile property of perivascular adipose tissue (PVAT) is abolished through an endothelium‐dependent pathway in obesity. C1q/tumor necrosis factor‐related protein (CTRP)9 improved endothelial function by promoting endothelium‐dependent vasodilatation. The aims of this study were to investigate whether CTRP9 improves the anti‐contractile effect of PVAT and protects against PVAT dysfunction in obese mice. The mice were treated with a high‐fat diet with or without CTRP9 treatment. Thoracic aortas with or without PVAT (PVAT+ or PVAT?) were prepared, and concentration‐dependent responses to phenylephrine were measured. Obese mice showed a significantly increased contractile response, which was suppressed by CTRP9 treatment both with and without PVAT. PVAT significantly reduced the anti‐contractile effect in obese mice, which was partially restored by CTRP9 treatment. Treatment of the aortic rings (PVAT+) with inhibitors of AMP protein kinase (AMPK), Akt and endothelial nitric oxide synthase (eNOS) attenuated the beneficial effect of CTRP9 on PVAT. Similar results were observed when we pretreated the aortic rings with CTRP9 ex vivo. CTRP9 significantly enhanced the phosphorylation levels of AMPK, Akt and eNOS, and reduced superoxide production and TNF‐α levels in PVAT from obese mice. Our study suggests that CTRP9 enhanced the anti‐contractile effect of PVAT and improved PVAT function by activating the AMPK‐eNOS pathway in obese mice.     

Chronic moderate alcohol consumption relieves high‐fat high‐cholesterol diet‐induced liver fibrosis in a rat model

Nonalcoholic fatty liver disease is a worldwide health issue and chronic alcohol consumption may have different effects on this disease. This study explored the role of chronic moderate alcohol consumption on high‐fat high‐cholesterol (HFHC) diet‐induced liver fibrosis in a rodent model. Male Sprague–Dawley rats were divided into five groups: standard chow group, standard chow plus Er Guo Tou (EGT, a Chinese spirit made from fermented cereals) group, HFHC group, HFHC plus EGT group, and HFHC plus pure ethanol (EtOH) group. Rats were fed standard chow or HFHC chow for 12 weeks. EGT or pure ethanol was administrated at a daily dose of 4 g/kg body weight via intra‐gastric gavage from week 4. At the end of week 12, hematoxylin and eosin staining, Sirius red and immunohistochemistry of liver sections were examined. The hepatic expression of F4/80, TNF‐α, IL‐1β, IL‐6, CXCL1, CXCL2, α‐SMA, Collagen, TGF‐β, MMP2, MMP9, and TIMP1 was calculated. Both moderate EGT and pure ethanol did not increase plasma endotoxin in the portal vein comparing with the FHFC group. EGT and pure ethanol did not improve hepatic inflammation, but ameliorated liver fibrosis in histology. Moderate EGT and pure ethanol ameliorated HFHC diet‐induced activation of Kupffer cells and hepatic stellate cells. In conclusion, chronic moderate EGT and pure ethanol could ameliorate HFHC diet‐induced liver fibrosis.     

Atorvastatin improves insulin sensitivity in mice with obesity induced by monosodium glutamate

Aim:

To examine the mechanisms underlying the effects of atorvastatin on glucose and lipid metabolism.

Methods:

Mice with insulin resistance and obesity induced by monosodium glutamate (MSG) were used. Atorvastatin (80 mg·kg⁻¹·d⁻¹) or vehicle control treatment was given orally once a day for 30 days. Plasma levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and free fatty acids were monitored. Serum insulin and glucose concentrations were used to calculate the insulin resistance index and insulin sensitivity index using a homeostasis model. Body length, waistline circumference, intraperitoneal adipose tissue mass, and total body mass were measured. Semi-quantitative RT-PCR and Western analysis were used to determine the expression of inflammatory factors and proteins involved in inflammation signaling pathways.

Results:

Atorvastatin improved insulin sensitivity, ameliorated glucose tolerance, and decreased plasma levels of total cholesterol, triglycerides, LDL-C, HDL-C and free fatty acids. Semi-quantitative RT-PCR and Western analysis revealed increased expression of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in serum and adipose tissue in MSG obese mice. Atorvastatin treatment decreased expression of IL-6, TNF-α, nuclear factor κB (NF-κB) and I-kappa-B (IκB) kinase-β, but increased the expression of IκB, in adipose tissue.

Conclusion:

Atorvastatin is a potential candidate for the prevention and therapy of diseases associated with insulin resistance such as type 2 diabetes mellitus and cardiovascular disease. One possible mechanism underlying the effects of atorvastatin on glucose and lipid metabolism may be to ameliorate a state of chronic inflammation.     

Eugenosedin‐A prevents hyperglycaemia,hyperlipidaemia and lipid peroxidation in C57BL/6J mice fed a high‐fat diet

Objectives Eugenosedin‐A is a serotonin (5‐hydroxytryptamine; 5‐HT) 5‐HT_{1b /2a} and _α1/α2/β1‐adrenoceptor blocker with anti‐oxidative, anti‐inflammatory and free‐radical scavenging activities. Previous reports demonstrated that 5‐HT_2a blockers could diminish hyperlipidaemia. This study therefore aimed to investigate the possible uses and mechanisms of eugenosedin‐A and other agents in treating hyperlipidaemia. Methods C57BL/6J mice were randomly divided into seven groups, fed a regular diet or a high‐fat diet alone or supplemented with one of five agents: eugenosedin‐A, ketanserin, prazosin, propranolol or atorvastatin (5 mg/kg p.o.) for 8 weeks. Key findings Compared with the regular diet, the mice fed the high‐fat diet had significantly higher body weight and glucose, insulin and lipid levels. Brain malondialdehyde concentration was increased and liver glutathione peroxidase activity decreased. Addition of eugenosedin‐A to the high‐fat diet resulted in less weight gain and reduced hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. Lipid and glucose homeostasis were related to decreased hepatic lipogenesis mRNAs and proteins (sterol regulatory element binding protein 1a, fatty acid synthase, sterol‐CoA desaturase) and restored adipose peroxisome proliferator‐activated receptor γ expression. Eugenosedin‐A also enhanced low‐density lipoprotein receptor mRNA expression. Conclusions Eugenosedin‐A may improve plasma lipid metabolism by increasing low‐density lipoprotein receptor and peroxisome proliferator‐activated receptor γ expression and diminishing sterol regulatory element binding protein 1a, fatty acid synthase and sterol‐CoA desaturase. Reduction of plasma glucose and lipid levels may, in turn, reduce insulin concentration, which would explain the marked improvement in obesity‐related hyperglycaemia and hyperlipidaemia. Furthermore, eugenosedin‐A affected malondialdehyde concentration and glutathione peroxidase activity, suggesting it may have anti‐peroxidation effects in mice fed a high‐fat diet.     

Insulin therapy stimulates lipid synthesis and improves endocrine functions of adipocytes in dietary obese C57BL/6 mice

Aim:

To evaluate whether insulin intervention could affect the metabolic and endocrine functions of adipose tissue.

Methods:

C57BL/6 mice were fed on a high-fat-diet for 12−16 weeks to induce insulin resistance. Insulin intervention was administered in the high-fat-diet mice for 4 weeks at 12 weeks (early insulin treatment) or 16 weeks (late insulin treatment). Intraperitoneal glucose tolerance tests were performed before and after insulin treatment. Expression levels of factors involved in the triglyceride synthesis and endocrine functions of adipose tissue including phosphoenolpyruvate carboxykinase (PEPCK-C), fatty acid synthase (FAS), aquaporin 7 (AQP7), adiponectin, visfatin, and interleukin-6 (IL-6) were determined by Western blot.

Results:

In the obese mice, glucose tolerance was impaired; triglyceride content was increased in the liver tissue; protein expression of FAS and adiponectin was decreased; expression of visfatin was increased in adipose tissue. After 4-week insulin treatment, glucose tolerance was improved; triglyceride content was decreased in the liver and skeletal muscle; expression of PEPCK-C, FAS, and adiponectin was increased in the adipose tissue; IL-6 and AQP7 expression was reduced in the fat. Early insulin treatment had better effect in increasing the expression of FAS and PEPCK-C and decreasing the expression of IL-6.

Conclusion:

These results indicate that insulin can target adipocytes for improvement of insulin sensitivity through stimulating triglyceride synthesis and partly improving endocrine functions.     

奥贝胆酸对2型糖尿病KKAy小鼠的糖脂稳态影响

目的:研究奥贝胆酸(obeticholic acid,OCA)对自发性2型糖尿病KKAy小鼠的抗糖尿病作用.方法:将KKAy小鼠随机分为对照组(Control)和奥贝胆酸组(OCA,10 mg·kg-1),每组9只,ig给药,qd,连续6周.实验期间检测小鼠的体重、摄食量、摄水量、血糖、血脂、糖化血红蛋白和胰岛素水平,...     

机械加载改善高脂饮食诱导的肥胖相关骨丢失

目的 探究脉冲式关节机械加载对高脂饮食诱导的肥胖小鼠骨丢失的改善作用。方法 将 45只雌性C57BL/6小鼠随机分为普通饮食对照组（Sham组）、高脂饮食模型组（HF组）和高脂加载治疗组（HF+L组）,每组 15只。HF组和 HF+L组高脂饮食喂养 4周后,HF+L组进行 4周的机械加载治疗（加载条件为 1 N,10 Hz,3 min/d,每周连续加载 5 d）。治疗结束后测量 3组小鼠体质量指数（BMI）、全身体脂含量和双侧股骨的骨密度。使用 HE染色和MacNeal’s染色分析观察股骨的组织病理改变,使用 Western blot检测成骨生成相关蛋白［碱性磷酸酶（ALP）、Runt相关转录因子 2（RUNX2）］和脂肪生成相关蛋白［过氧化物酶体增殖物激活受体 γ（PPARγ）、CCAAT/增强子结合蛋白 α（C/EBPα）］的表达。结果 与 Sham组相比,HF组小鼠的体脂含量和 BMI升高,骨密度变化率和骨量变化率显著下降,骨小梁面积明显减少,骨髓脂肪细胞增多。机械加载治疗后,HF+L组的骨密度、骨小梁面积比 HF组明显升高,脂肪细胞的数目和面积比 HF 组显著降低（P＜0.05）。Western blot 分析结果表明,HF+L 组与 HF 组相比,ALP 和RUNX2的表达显著升高,C/EBPα和 PPARγ的表达明显降低（均P＜0.05）。结论 机械加载能够有效缓解由肥胖引起的低骨密度和低骨量,其治疗作用可能通过促进成骨分化和抑制脂肪生成来改善骨丢失。     

结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的影响结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的影响

目的研究结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的胰岛素抵抗是否有改善作用。方法建立胰岛素抵抗模型后分为模型、结合亚油酸和罗格列酮组,观察结合亚油酸对MSG小鼠肥胖、葡萄糖代谢、胰岛素抗性、血及脂肪组织中TNF-α含量等的影响。结果结合亚油酸使MSG小鼠体重增长减少,体型明显改变,但对MSG小鼠异常的胰岛素和葡萄糖耐量、高胰岛素血症及脂肪组织中TNF-α含量升高均无改善,使胰岛素敏感指数明显降低。结论结合亚油酸对MSG小鼠有一定减肥作用,对MSG小鼠的胰岛素抵抗无改善作用。     

Cardiolipin profiles as a potential biomarker of mitochondrial health in diet‐induced obese mice subjected to exercise,diet‐restriction and ephedrine treatment

Cardiolipin (CL) is crucial for mitochondrial energy metabolism and structural integrity. Alterations in CL quantity or CL species have been associated with mitochondrial dysfunction in several pathological conditions and diseases, including mitochondrial dysfunction‐related compound attrition and post‐market withdrawal of promising drugs. Here we report alterations in the CL profiles in conjunction with morphology of soleus muscle (SM) and brown adipose tissue (BAT) in diet‐induced obese (DIO) mice, subjected to ephedrine treatment (EPH: 200 mg kg^–1 day^–1 orally), treadmill exercise (EX: 10 meters per min, 1 h per day), or dietary restriction (DR: 25% less of mean food consumed by the EX group) for 7 days. Mice from the DR and EPH groups had a significant decrease in percent body weight and reduced fat mass compared with DIO controls. Morphologic alterations in the BAT included brown adipocytes with reduced cytoplasmic lipid droplets and increased cytoplasmic eosinophilia in the EX, DR and EPH groups. Increased cytoplasmic eosinophilia in the BAT was ultrastructurally manifested by increased mitochondrial cristae, fenestration of mitochondrial cristae, increased electron density of mitochondrial matrix, and increased complexity of shape and elongation of mitochondria. Mitochondrial ultrastructural alterations in the SM of the EX and DR groups included increased mitochondrial cristae, cup‐shaped mitochondria and mitochondrial degeneration. All four CL species (tri‐linoleoyl‐mono‐docosahexaenoyl, tetralinoleoyl, tri‐linoleoyl‐mono‐oleoyl, and di‐linoleoyl‐di‐oleoyl) were increased in the BAT of the DR and EPH groups and in the SM of the EPH and EX groups. In conclusion, cardiolipin profiling supported standard methods for assessing mitochondrial biogenesis and health, and may serve as a potential marker of mitochondrial dysfunction in preclinical toxicity studies. Copyright © 2014 John Wiley & Sons, Ltd.     

Vitamin B complex mitigates cardiac dysfunction in high‐methionine diet‐induced hyperhomocysteinemia

This research is designed to test the hypothesis that elevated homocysteine (Hcy) levels in vivo, caused by a deficit in vitamin B complex, promote changes in cardiac function and redox status that lead to heart failure. In order to conduct the study, we used adult male Wistar albino rats (n = 30; 4 weeks old; 100 ± 15 g body weight). Hyperhomocysteinaemia (HHcy) in these animals was achieved by dietary manipulation. For 4 weeks, the animals were fed with a standard rodent chow (control, CF), a diet enriched in methionine with no deficiency in B vitamins (i.e., folic acid, B6 and B12) (HMNV) or a diet enriched in methionine and deficient in B vitamins (HMLV). After 28 days of dietary manipulation, all animals were killed. The rat hearts were isolated and retrogradely perfused according to the Langendorff technique at a gradually increasing perfusion pressure. We found a negative correlation between elevated serum Hcy and total body and heart weight. The maximum rate of left ventricular pressure development was significantly increased in the HMNV group compared with in the other groups. Systolic left ventricular pressure was significantly changed in all groups. HHcy induces remodelling of the cardiac tissues, as moderate HHcy is associated with more prominent interstitial and perivascular fibrosis. Our results suggest that a high methionine diet without vitamin B complex causes profound negative effects associated with HHcy.     

Pioglitazone can ameliorate insulin resistance in low-dose streptozotocin and high sucrose-fat diet induced obese rats

Aim: To investigate the effect of the peroxisome proliferator-activator receptor (PPAR)-γ agonist, pioglitazone, on insulin resistance in low-dose streptozotocin and high sucrose-fat diet induced obese rats. Methods: Normal female Wistar rats were injected intraperitoneally with low-dose streptozotocin (STZ, 30mg/kg) and fed with a high sucrose-fat diet for 8 weeks. Pioglitazone (20mg/kg) was administered orally to the obese and insulin-resistant rats for 28d. Intraperitoneal glucose tolerance tests, insulin tolerance tests and gluconeogenesis tests were car ried out over the last 14d. At the end of d 28 of the treatment, serums were collected for biochemical analysis. Glucose transporter 4 (GLUT4) and insulin receptor substrate-1 (IRS-1) protein expression in the liver and skeletal muscle were detected using Western blotting. Results: Significant insulin resistance and obesity were observed in low-dose STZ and high sucrose-fat diet induced obese rats. Pioglitazone (20mg/kg) treatment significantly decreased serum insulin,triglyceride and free fatty acid levels, and elevated high density lipoprotein-cholesterol (HDL-C) levels. Pioglitazone also lowered the lipid contents in the liver and muscles of rats undergoing treatment. Gluconeogenesis was inhibited and insulin sensitivity was improved markedly. The IRS-1 protein contents in the liver and skeletal muscles and the GLUT4 contents in skeletal muscle were elevated significantly. Conclusion: The data suggest that treatment with pioglitazone improves insulin sensitivity in low-dose STZ and high sucrose-fat diet induced obese rats. The insulin sensitizing effect may be associated with ameliorating lipid metabolism, reducing hyperinsulinemia, inhibiting gluconeogenesis, and increasing IRS-1 and GLUT4 protein expression in insulin-sensitive tissues.