Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver

Our previous study has shown that reduced insulin resistance (IR) was one of the possible mechanisms for the therapeutic effect of silibinin on non-alcoholic fatty liver disease (NAFLD) in rats. In the present study, we investigated the pathways of silibinin in regulating hepatic glucose production and IR amelioration. Forty-five 4- to 6-week-old male Sprague Dawley rats were divided into a control group, an HFD group (high-fat diet for 6 weeks) and an HFD + silibinin group (high-fat diet + 0.5 mg kg^-1·day^-1 silibinin, starting at the beginning of the protocol). Both subcutaneous and visceral fat was measured. Homeostasis model assessment-IR index (HOMA-IR), intraperitoneal glucose tolerance test and insulin tolerance test (ITT) were performed. The expression of adipose triglyceride lipase (ATGL) and of genes associated with hepatic gluconeogenesis was evaluated. Silibinin intervention significantly protected liver function, down-regulated serum fat, and improved IR, as shown by decreased HOMA-IR and increased ITT slope. Silibinin markedly prevented visceral obesity by reducing visceral fat, enhanced lipolysis by up-regulating ATGL expression and inhibited gluconeogenesis by down-regulating associated genes such as Forkhead box O1, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Silibinin was effective in ameliorating IR in NAFLD rats. Reduction of visceral obesity, enhancement of lipolysis and inhibition of gluconeogenesis might be the underlying mechanisms.     

Liver mitochondrial function and redox status in an experimental model of non-alcoholic fatty liver disease induced by monosodium L-glutamate in rats

The purpose of this work was to determine if mitochondrial dysfunction is involved in the development of non-alcoholic fatty liver disease (NAFLD). Using a model of obesity induced by the neonatal treatment of rats with monosodium l-glutamate (MSG), several parameters of liver mitochondrial function and their impact on liver redox status were evaluated. Specifically, fatty acid β-oxidation, oxidative phosphorylation and Ca²⁺-induced mitochondrial permeability transition were assessed in isolated liver mitochondria, and reduced glutathione (GSH), linked thiol contents and the activities of several enzymes involved in the control of redox status were measured in the liver homogenate. Our results demonstrate that liver mitochondria from MSG-obese rats exhibit a higher β-oxidation capacity and an increased capacity for oxidising succinate, without loss in the efficiency of oxidative phosphorylation. Also, liver mitochondria from obese rats were less susceptible to the permeability transition pore (PTP) opening induced by 1.0 μM CaCl₂. Cellular levels of GSH were unaffected in the livers from the MSG-obese rats, whereas reduced linked thiol contents were increased. The activities of glucose-6-phosphate dehydrogenase, glutathione reductase and glutathione peroxidase were increased, while catalase activity was unaffected and superoxide dismutase activity was reduced in the livers from the MSG-obese rats. In this model of obesity, liver fat accumulation is not a consequence of mitochondrial dysfunction. The enhanced glucose-6-phosphate dehydrogenase activity observed in the livers of MSG-obese rats could be associated with liver fat accumulation and likely plays a central role in the mitochondrial defence against oxidative stress.     

“Is obesity linked to aging?”: Adipose tissue and the role of telomeres

Obesity is a condition in which excess or abnormal fat accumulation may present with adverse effects on health and decreased life expectancy. Increased body weight and adipose tissue accumulation amplifies the risk of developing various age-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, musculoskeletal disorders, respiratory diseases and certain types of cancer. This imbalance in body composition and body weight is now recognized as a state of increased oxidative stress and inflammation for the organism. Increasing oxidative stress and inflammation affect telomeres. Telomeres are specialized DNA-protein structures found at the ends of eukaryotic chromosomes and serve as markers of biological aging rate. They also play a critical role in maintaining genomic integrity and are involved in age-related metabolic dysfunction. Erosion of telomeres is hazardous to healthy cells, as it is a known mechanism of premature cellular senescence and loss of longevity. The association of telomeres and oxidative stress is evident in cultured somatic cells in vitro, where oxidative stress enhances the process of erosion with each cycle of replication. Shorter telomeres have been associated with increasing body mass index, increased adiposity, and more recently with increasing waist to hip ratio and visceral excess fat accumulation. Furthermore, many of the metabolic imbalances of obesity (e.g. glycemic, lipidemic, etc.) give rise to organ dysfunction in a way that resembles the accelerated aging process. This article is a non-systematic review of the evidence linking obesity and accelerated aging processes as they are regulated by telomeres.     

Management of obesity in menopause: Diet,exercise, pharmacotherapy and bariatric surgery

Menopause is characterized by the progressive reduction of estrogens resulting to cessation of menses. It is associated with an increase of cardiovascular risk factors such as hyperglycemia, hypertension, dyslipidemia and of abdominal and/or selective visceral fat mass deposition. Obesity, a modern day epidemic, is promoted by an obesogenic environment that interacts with the genetic background. The result is a positive energy balance materialized by the accumulation of the adipose tissue. This process is marked by great individual variation. Obesity is also associated with the presence of cardiovascular risk factors. In this review, the main pathophysiologic processes for the increase of obesity in menopause and the possible effects of pre-menopausal obesity regarding the cessation of ovarian function are described. The interactions among the hypothalamic-pituitary-gonadal and -adrenal (stress system) axes and the environment are explored. Furthermore, the therapeutic means that a clinician can employ to help menopausal women to overcome the menopause-associated increase of their weight are developed.     

Effect of Regular Exercise on the Histochemical Changes of d-Galactose-Induced Oxidative Renal Injury in High-Fat Diet-Fed Rats

Renal lipid accumulation exhibits slowly developing chronic kidney disease and is associated with increased oxidative stress. The impact of exercise on the obese- and oxidative stress-related renal disease is not well understood. The purpose of this study was to investigate whether a high-fat diet (HFD) would accelerate d-galactose-induced aging process in rat kidney and to examine the preventive effect of regular exercise on the obese- and oxidative stress-related renal disease. Oxidative stress was induced by an administration of d-galactose (100 mg/kg intraperitoneally injected) for 9 weeks, and d-galactose-treated rats were also fed with a high-fat diet (60% kcal as fat) for 9 weeks to induce obesity. We investigated the efficacy of regular exercise in reducing renal injury by analyzing Nε-carboxymethyllysine (CML), 8-hydroxygluanine (8-OHdG) and apoptosis. When rats were fed with a HFD for 9 weeks in d-galactose-treated rats, an increased CML accumulation, oxidative DNA damage and renal podocyte loss were observed in renal glomerular cells and tubular epithelial cells. However, the regular exercise restored all these renal changes in HFD plus d-galactose-treated rats. Our data suggested that long-term HFD may accelerate the deposition of lipoxidation adducts and oxidative renal injury in d-galactose-treated rats. The regular exercise protects against obese- and oxidative stress-related renal injury by inhibiting this lipoxidation burden.     

Obesity,adiposity, and dyslipidemia: A consensus statement from the National Lipid Association

The term “fat” may refer to lipids as well as the cells and tissue that store lipid (ie, adipocytes and adipose tissue). “Lipid” is derived from “lipos,” which refers to animal fat or vegetable oil. Adiposity refers to body fat and is derived from “adipo,” referring to fat. Adipocytes and adipose tissue store the greatest amount of body lipids, including triglycerides and free cholesterol. Adipocytes and adipose tissue are active from an endocrine and immune standpoint. Adipocyte hypertrophy and excessive adipose tissue accumulation can promote pathogenic adipocyte and adipose tissue effects (adiposopathy), resulting in abnormal levels of circulating lipids, with dyslipidemia being a major atherosclerotic coronary heart disease risk factor. It is therefore incumbent upon lipidologists to be among the most knowledgeable in the understanding of the relationship between excessive body fat and dyslipidemia. On September 16, 2012, the National Lipid Association held a Consensus Conference with the goal of better defining the effect of adiposity on lipoproteins, how the pathos of excessive body fat (adiposopathy) contributes to dyslipidemia, and how therapies such as appropriate nutrition, increased physical activity, weight-management drugs, and bariatric surgery might be expected to impact dyslipidemia. It is hoped that the information derived from these proceedings will promote a greater appreciation among clinicians of the impact of excess adiposity and its treatment on dyslipidemia and prompt more research on the effects of interventions for improving dyslipidemia and reducing cardiovascular disease risk in overweight and obese patients.     

The “Big Bang” in obese fat: Events initiating obesity‐induced adipose tissue inflammation

Obesity is associated with the accumulation of pro‐inflammatory cells in visceral adipose tissue (VAT), which is an important underlying cause of insulin resistance and progression to diabetes mellitus type 2 (DM2). Although the role of pro‐inflammatory cytokines in disease development is established, the initiating events leading to immune cell activation remain elusive. Lean adipose tissue is predominantly populated with regulatory cells, such as eosinophils and type 2 innate lymphocytes. These cells maintain tissue homeostasis through the excretion of type 2 cytokines, such as IL‐4, IL‐5, and IL‐13, which keep adipose tissue macrophages (ATMs) in an anti‐inflammatory, M2‐like state. Diet‐induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in VAT, characterized by IFN‐γ. A key event is a shift of ATMs toward an M1 phenotype. Recent studies show that obesity‐induced adipocyte hypertrophy results in upregulated surface expression of stress markers. Adipose stress is detected by local sentinels, such as NK cells and CD8⁺ T cells, which produce IFN‐γ, driving M1 ATM polarization. A rapid accumulation of pro‐inflammatory cells in VAT follows, leading to inflammation. In this review, we provide an overview of events leading to adipose tissue inflammation, with a special focus on adipose homeostasis and the obesity‐induced loss of homeostasis which marks the initiation of VAT inflammation.     

Effects of alternations (10 days) of high-fat with normal diet on liver lipid infiltration, fat gain, and plasma metabolic profile in rats

The purpose of the present study was to test the hypothesis that short-term alternations of high-fat with normal chow feeding result in higher fat accumulation in liver than continuous intake of the same high-fat diet. Male Sprague-Dawley rats (7 weeks of age) were divided into 3 groups according to diet composition: standard chow (SD; 12,5% kcal as fat), high-fat (HF; 42% kcal as fat), and food cycles (FC) consisting of 10-day alternations between HF and SD diets beginning with the high-fat diet. Rats in each of these 3 groups were sacrificed after 10, 30, and 50 days (n = 10 rats/sub-groups). Energy intake, body weight, liver and muscle relative weights were not significantly (P > 0.05) different between FC- and HF-fed rats. Using the total energy intake for the 50-day period, it was calculated that approximately 30% less calories as fat was ingested in the FC- compared to the HF-fed rats. In spite of this, liver lipid infiltration as well as fat accretion in abdominal adipose tissues were increased (P < 0.01) similarly in FC- and HF-fed rats. Plasma FFA and insulin levels depicted strong tendencies (P < 0.07) to be higher in FC- than in continuous HF-fed rats at the end of the 50-day period. These results indicate that, despite a 30% reduction in ingested lipids, alternations of HF with normal chow diet compared to the continuous hyperlipidic diet caused the same level of infiltration of lipids in the liver and in the abdominal adipose tissues and, to a certain extent, may even result in a larger deterioration of the metabolic profile.     

Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men

A high-fat, high-calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic defects to the development of hyperglycaemia and type 2 diabetes is controversial. Accumulation of excess fat in muscle and adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation. The aim of the current study was to investigate acute effects of short-term fat overfeeding on glucose and insulin metabolism in young men. We studied the effects of 5 days' high-fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function by ³¹P magnetic resonance spectroscopy, and gene expression by qrt-PCR and microarray in 26 young men. Hepatic glucose production and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high-fat feeding. Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High-fat feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High-fat overfeeding increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.     

高脂饮食肥胖模型小鼠脂肪组织受体相互作用蛋白140基因的表达

背景：受体相互作用蛋白140基因敲除小鼠可通过增加线粒体生物功能、脂肪酸氧化、氧化磷酸化等代谢途径来抵抗高脂饮食诱导的肥胖。 目的：构建高脂饮食致肥胖模型小鼠,观察脂肪组织受体相互作用蛋白140 mRNA表达水平变化及胰岛素抵抗的关系。 方法：将C57BL/6J雄性小鼠随机分为对照组和高脂饮食组,分别喂养14周后,测量2组小鼠体质量,选取高脂饮食组中体质量大于对照组小鼠平均体质量20%的小鼠作为肥胖组小鼠。 结果与结论：高脂饮食组小鼠中有12只符合标准计入肥胖组。肥胖组小鼠三酰甘油、总胆固醇、空腹血糖、空腹胰岛素水平和胰岛素抵抗指数均明显高于对照组(P < 0.05或P < 0.01);肥胖组小鼠脂肪组织中受体相互作用蛋白140 mRNA的表达高于对照组(P < 0.05);且小鼠脂肪组织受体相互作用蛋白140 mRNA表达水平与三酰甘油水平、胰岛素抵抗指数呈正相关(r=0.526,P < 0.05;r=0.465,P < 0.05),而与总胆固醇、空腹血糖、空腹胰岛素水平无相关性(P > 0.05)。 中国组织工程研究杂志出版内容重点：肾移植;肝移植;移植;心脏移植;组织移植;皮肤移植;皮瓣移植;血管移植;器官移植;组织工程全文链接：     

Telmisartan prevents high-fat diet-induced hypertension and decreases perirenal fat in rats

We sought to investigate the effects of telmisartan on high-fat diet-induced hypertension and to explore the possible underlying mechanisms.Rats receiving high-fat diet were randomly divided into two groups,the telmisartan group(n = 9) and the high-fat diet group(n = 10).The control group consisted of age-matched rats on a regular diet(n = 10).At the end of the treatment,the body weight,blood pressure,insulin sensitivity and serum adiponectin levels of all rats were examined,and their visceral fat was extracted and weighed.Our results showed that telmisartan improved insulin resistance and dyslipidemia and increased serum adiponectin levels.Telmisartan also lowered both systolic blood pressure and diastolic blood pressure,and decreased the accumulation of perirenal fat associated with high-fat diet.Furthermore,telmisartan increased adiponectin mRNA expression in the perirenal fat.Correlation analysis showed that both systolic blood pressure and diastolic blood pressure were positively correlated with perirenal fat.These effects of telmisartan may be mediated through decreases in perirenal fat and contributed to the improvement of perirenal fat function.Our findings suggested a strong link between perirenal fat and high-fat diet-induced hypertension,and identified telmisartan as a potential drug for the treatment of obesity-related hypertension.     

Resveratrol prevents high-fat diet-induced obesity and oxidative stress in rabbits

The rapid epidemiological progression of obesity worldwide has been associated with increased consumption of diets, rich in fat and sugar. Mediterranean diets rich in resveratrol are associated with reduced risk of obesity and oxidative stress. The aim of the experiment was to investigate the protective effect of resveratrol on high fat diet (HFD) induced obesity and oxidative stress changes in rabbits. Thirty rabbits divided into six groups of five animals each were used for the experiment: Group 1?=?control (C), Group 2?=?high fat diet (HFD) only, Group 3?=?resveratrol 200?mg/kg (R200), Group 4?=?resveratrol 400?mg/kg (R400), Group 5?=?HFD?+?R200 and group 6?=?HFD?+?R400. After four weeks of treatment, the HFD group showed significant (P?<?0.05) increase in body weight of the animals, when compared with the groups co- administered with resveratrol and high-fat diet, and resveratrol alone groups. Activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) decreased significantly (P?<?0.05) in the HFD groups co-administered with resveratrol when compared with HFD group only. In conclusion, administration of HFD to rabbits increased body weight and decreased antioxidant enzyme activities which were mitigated by resveratrol administration.     

Diet-induced obesity in the short-day-lean Brandt's vole

To test the hypothesis that mammals that show decrease in body mass under short-day condition should be resistant to high-fat induced obesity, we traced the changes of energy balance in a wild rodent, Brandt's voles (Lasiopodomys brandtii), which were acclimated to either long day (16 L: 8D, LD) or short day (8 L: 16D, SD) and fed either low-fat diet (LFD) or high-fat diet (HFD) in each photoperiodic manipulation. We found that Brandt's vole was not resistant to high-fat diet-induced obesity and SD, not HFD, induced the elevation in basal metabolic rate, the maximal rate of oxygen consumption after norepinephrine injection, and uncoupling protein 1 content in brown adipose tissue. HFD caused the increase in apparent digestibility and body fat mass, and the decrease in energy intake in both LD and SD voles. The enhancement of energy absorption associated with small intestine tissue recruitment can compensate the lower energy intake, which may contribute to the high-fat diet-induced body fat deposition. Thus, a decrease in body-weight gain but has no resistance to high-fat induced obesity implies an evolutionary and adaptive mechanism which is a benefit for their winter survival.     

Oxidative stress as pathogenesis of cardiovascular risk associated with metabolic syndrome

Metabolic syndrome (MetS) is characterized by accumulation of visceral fat associated with the clustering of metabolic and pathophysiological cardiovascular risk factors: impaired glucose tolerance, dyslipidemia, and hypertension. Although the definition of MetS is different among countries, visceral obesity is an indispensable component of MetS. A growing body of evidence suggests that increased oxidative stress to adipocytes is central to the pathogenesis of cardiovascular disease in MetS. Increased oxidative stress to adipocytes causes dysregulated expression of inflammation-related adipocytokines in MetS, which contributes to obesity-associated vasculopathy and cardiovascular risk primarily through endothelial dysfunction. The purpose of present review is to unravel the mechanistic link between oxidative stress and cardiovascular risk in MetS, focusing on insulin resistance, hypertension, and atherosclerosis. Then, therapeutic opportunities translated from the bench to bedside will be provided to develop novel strategies to cardiovascular risk factors in MetS.     

Food restriction and refeeding induces changes in lipid pathways and fat deposition in the adipose and hepatic tissues in rats with diet-induced obesity

The aim of this study was to determine the effects of successive cycles of a moderately restrictive diet and refeeding with a high-fat diet on the metabolism of the adipose and hepatic tissues of obese rats. Rats were assigned to the following groups: a chow diet; a high-fat diet; a moderate caloric restriction; or a moderate caloric restriction plus refeeding. Some animals in each group were given [1-(14)C]triolein intragastrically, while others received an intraperitoneal injection of 3 mCi (3)H(2)O. All animals were killed by decapitation. The retroperitoneal, visceral epididymal and omental white adipose tissues, brown adipose tissue, liver and blood were immediately removed. The lipid uptake from the diet, in vivo rate of lipogenesis, percentage of fat, lipid profile and leptin concentration were analysed. The high-fat diet promoted an increase in fatty liver (P ≤ 0.05), adiposity mass (P ≤ 0.05) and the plasma concentration of leptin (P ≤ 0.05) and a decreased lipid uptake in white adipose tissue depots (P ≤ 0.05) in relation to the chow diet. The moderate caloric restriction did not reverse the changes promoted by the high-fat diet but induced a small decrease in adiposity, which was reversed after refeeding, and the animals maintained a dyslipidaemic profile and high fat deposition in the liver. We can conclude that the high-fat diet and subsequent moderate caloric restriction plus refeeding increased the risks of developing visceral obesity, dyslipidaemia and non-alcoholic fatty liver disease, which suggests that this type of experimental protocol can be used to study mechanisms related to the metabolic syndrome.     

枸骨叶水提物对小鼠肥胖的预防作用及对脂肪分化的影响

目的:研究枸骨叶水提物(ICAE)对高脂饮食(HFD)小鼠肥胖的预防作用及对脂肪分化的影响.方法:本研究采用HFD诱导小鼠肥胖,同时灌胃给予ICAE,以奥利司他(orlistat)为阳性对照药。39只昆明雄性小鼠分成4组,包括对照组(n=10)、肥胖模型组(n=9)、orlistat治疗组(n=10)和ICAE治疗组(n=10)。以体重、腹内和皮下脂肪含量、肝重以及血清甘油三酯(TG)和总胆固醇(TC)水平为指标,观察ICAE对肥胖的预防作用;在实验第5周,连续5 d监测ICAE对小鼠24 h平均摄食量的影响;HE染色观察ICAE对脂肪组织的影响。分离和培养大鼠附睾来源的前脂肪细胞,尼罗红染色观察ICAE对分化脂肪细胞内脂滴形态的影响,Western blot法检测ICAE对细胞内过氧化物酶体增殖物激活受体γ(PPARγ)、脂滴包被蛋白1(Plin1)及激素敏感性脂肪酶(HSL)蛋白表达的影响。结果:ICAE可以显著抑制HFD引起的小鼠体重、腹内和皮下脂肪含量以及肝重的增加(P<0.01),并且显著降低血清TC和TG水平(P<0.01),但是对摄食量无显著影响;HE染色显示,ICAE能够显著减少HFD引起的白色脂肪细胞肥大。此外,在原代培养的大鼠分化脂肪细胞中,ICAE可以显著抑制细胞内脂滴的积累,并且显著下调脂肪分化关键转录因子PPARγ以及脂肪分化标志物Plin1和HSL的蛋白水平(P<0.01)。结论:ICAE对HFD诱导的小鼠肥胖具有预防作用,但对摄食量无明显影响;ICAE可以显著抑制脂肪分化过程,此作用可能与下调PPARγ的蛋白表达有关。     

Oncostatin M in the development of metabolic syndrome and its potential as a novel therapeutic target

Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays an important role in various biologic actions, including cell growth, neuronal development, and inflammatory responses. Recently, we demonstrated the unique relationship between OSM and metabolic syndrome in mice. Mice lacking OSM receptor β subunit (OSMRβ^?/? mice) exhibited late-onset obesity. Before the onset of obesity, adipose tissue inflammation and insulin resistance were observed in OSMRβ^?/? mice. In addition, high-fat diet-induced metabolic disorders, including obesity, adipose tissue inflammation, insulin resistance, and hepatic steatosis, were aggravated in OSMRβ^?/? mice compared to those in wild-type mice. Consistent with these findings, OSM treatment dramatically improved these metabolic disorders in the mouse model of metabolic syndrome. Interestingly, OSM directly changed the phenotypes of adipose tissue macrophages toward anti-inflammatory M2 type. Furthermore, fatty acid content in the hepatocytes was decreased by OSM through expression regulation of several key enzymes of hepatic lipid metabolism. These findings suggest that OSM is a novel therapeutic target for metabolic syndrome.