Flavonoids from Camellia sinensis (L.) O. Kuntze seed ameliorates TNF-α induced insulin resistance in HepG2 cells

The aim of this study is to discuss the non-catechin flavonoids (NCF) from Camellia sinensis (L.) O. Kuntze seed improving TNF-α impaired insulin stimulated glucose uptake and insulin signaling. Flavonoids had anti-metabolic syndrome and anti-inflammatory properties. It had widely been known for biological activity of catechins in tea, but very few research reports discussed the biological activity of non-catechin flavonoids in tea seed. We used HepG2 cell to treat with 5 μM insulin or with 5 μM insulin + 30 ng/ml TNF-α. Detecting the glucose concentration of medium, insulin decreased the glucose levels of medium meant that insulin promoted glucose uptake into cells, but TNF-α inhibited the glucose uptake effect of insulin. Furthermore, insulin increased the protein expressions of IR, IRS-1, IRS-2, PI3K-α, Akt/PKB, GLUT-2, AMPK, GCK, pyruvate kinase, and PPAR-γ. TNF-α activated p65 and MAPKs (p38, JNK1/2 and ERK1/2), iNOS and COX-2 which worsened the insulin signaling expressions of IR, IRS-1, IRS-2, PI3K-α, Akt/PKB, GLUT-2, AMPK, GCK, pyruvate kinase, and PPAR-γ. We added NCF (500, 1000, 2000 ppm) to cell with insulin and TNF-α. Not only glucose levels of medium were lowered, and the protein expressions of insulin signaling were increased, but p38, JNK1/2, iNOS and COX-2 were also reduced. NCF could ameliorate TNF-α induced insulin resistance through inhibiting p38, JNK1/2, iNOS and COX-2, and suggested that it might be used in the future to help control insulin resistance. This finding is the first report to present the discovery.     

Adipocyte-derived exosomal miR-27a induces insulin resistance in skeletal muscle through repression of PPARγ

OBJECTIVE To explore increasingly exosomal serum miR-27 a derived from adipocytes could be taken up by skeletal muscle tissue and induce insulin resistance in skeletal muscle in obese state. METHODS The association between miR-27 a and insulin resistance in skeletal muscle was determined in obese children,high-fat diet-induced miR-27 a knockdown obese mice,db/db mice and C2C12 cells overexpressing miR-27 a.The crosstalk mediated by exosomal miR-27 a between adipose tissue and skeletal muscle was determined in C2C12 cel s incubated with conditioned medium prepared from palmitate-treated 3 T3-L1 adipocytes. RESULTS After knockdown miR-27 a in obese insulin resistance mice,impaired insulin resistance, glucose intolerance and insulin resistance of skeletal muscle were partly restored. In high-fat diet group, the expressions of IRS-1 and GLUT4 in glucose uptake signal pathway of skeletal muscle were significantly decreased, while the expression of IRS-1 and GLUT4 was restored after miR-27 a knockdown. The content of FABP4, a marker specific for exosomes from adipocytes, was detected in sera, skeletal muscle, supernatant of adipocytes and co-cultured C2C12 cells; furthermore,exosomal miR-27 a in serum and adipocyte supernatants were detect, and fluorescence co-localization experiments were conducted to detect whether the exosomal miR-27 a in serum is mainly derived from adipocyte; finally,we used the supernatant of adipose tissue to construct conditioned media to treat with C2C12 cells, and detected whether adipocytes derived exosomal miR-27 a could impaired glucose uptake signaling pathway of skeletal muscle. the expressions of PPARγ silencing high-fat diet induced C57 BL/6 J obese mouse model and adenovirus intervention miR-27 a knockdown model were examined,and a C2C12 cell model overexpressing miR-27 a in the absence or presence with rosiglitazone(PPARγ activator)were established to test glucose consumption, glucose uptake, and glucose uptake signaling pathways of skeletal muscle cells. CONCLUSION These results identify a novel crosstalk signaling pathway between adipose tissue and skeletal muscle in the development of insulin resistance, and indicate that adipose tissue-derived miR-27 a may play a key role in the development of obesity-triggered insulin resistance in skeletal muscle.     

益气养阴清热液对高血糖肥胖大鼠胰岛素抵抗的影响

目的观察益气养阴清热液(YYQ)对高血糖肥胖大鼠胰岛素抵抗的改善作用。方法采用高脂饲料加小剂量链脲佐菌素(STZ)诱导高血糖肥胖大鼠胰岛素抵抗,用YYQ治疗4wk。检测空腹血糖(FBG)、葡萄糖耐量(OGT)、血清胰岛素(INS)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)、游离脂肪酸(FFA)、红细胞膜胰岛素受体(INSR)、胰岛素钳夹实验下的葡萄糖输注率(GIR);测定肾周、附睾周围脂肪垫重量。同时测定YYQ对肝组织中IR-1、IRS-1mRNA表达的影响。结果YYQ治疗4wk后,大鼠血清中TC、TG、LDL-C、INS、FFA降低,OGT改善,而血清中HDL-C和GIR明显升高,INSR高、低亲和力受体数目均明显增多,肝组织中IR、IRS-1mRNA表达升高,各项指标均与模型组大鼠差异有显著性。结论YYQ对高血糖肥胖大鼠胰岛素抵抗有治疗作用,通过增加胰岛素受体数目而提高其胰岛素敏感性可能是其作用机制之一。     

Sarsasapogenin improves adipose tissue inflammation and ameliorates insulin resistance in high-fat diet-fed C57BL/6J mice

Insulin resistance is a major cause of type 2 diabetes and metabolic syndrome.Macrophage infiltration into obese adipose tissue promotes inflammatory responses that contribute to the pathogenesis of insulin resistance.Suppression of adipose tissue inflammatory responses is postulated to increase insulin sensitivity in obese patients and animals.Sarsasapogenin(ZGY)is one of the metabolites of timosaponin AIII in the gut,which has been shown to exert anti-inflammatory action.In this study,we investigated the effects of ZGY treatment on obesity-induced insulin resistance in mice.We showed that pretreatment with ZGY(80 mg·kg^?1·d^?1,ig,for 18 days)significantly inhibited acute adipose tissue inflammatory responses in LPS-treated mice.In high-fat diet(HFD)-fed obese mice,oral administration of ZGY(80 mg·kg^?1·d^?1,for 6 weeks)ameliorated insulin resistance and alleviated inflammation in adipose tissues by reducing the infiltration of macrophages.Furthermore,we demonstrated that ZGY not only directly inhibited inflammatory responses in macrophages and adipocytes,but also interrupts the crosstalk between macrophages and adipocytes in vitro,improving adipocyte insulin resistance.The insulin-sensitizing and anti-inflammatory effects of ZGY may result from inactivation of the IKK/NF-κB and JNK inflammatory signaling pathways in adipocytes.Collectively,our findings suggest that ZGY ameliorates insulin resistance and alleviates the adipose inflammatory state in HFD mice,suggesting that ZGY may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.     

Insulin resistance as a membrane microdomain disorder

Membrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling, but their role in the pathogenesis of insulin resistance has not been investigated. Detergent-resistant membrane microdomains (DRMs), isolated in the low density fractions, are highly enriched in cholesterol, glycosphingolipids and various signaling molecules. TNFalpha induces insulin resistance in type 2 diabetes, but its mechanism of action is not fully understood. We have found a selective increase in the acidic glycosphingolipid ganglioside GM3 in 3T3-L1 adipocytes treated with TNFalpha, suggesting a specific function for GM3. We were able to extend these in vitro observations to living animals using obese Zucker fa/fa rats and ob/ob mice, in which the GM3 synthase mRNA levels in the white adipose tissues are significantly higher than in their lean controls. In the DRMs from TNFalpha-treated 3T3-L1 adipocytes, GM3 levels were doubled, compared to results in normal adipocytes. Additionally, insulin receptor (IR) accumulations in the DRMs were diminished, while caveolin and flotillin levels were unchanged. GM3 depletion was able to counteract the TNFalpha-induced inhibition of IR accumulation into DRMs. Together, these findings provide compelling evidence that in insulin resistance the insulin metabolic signaling defect can be attributed to a loss of IRs in the microdomains due to an accumulation of GM3.     

Insulin resistance as a membrane microdomain disorder

Membrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling, but their role in the pathogenesis of insulin resistance has not been investigated. Detergent-resistant membrane microdomains (DRMs), isolated in the low density fractions, are highly enriched in cholesterol, glycosphingolipids and various signaling molecules. TNFalpha induces insulin resistance in type 2 diabetes, but its mechanism of action is not fully understood. We have found a selective increase in the acidic glycosphingolipid ganglioside GM3 in 3T3-L1 adipocytes treated with TNFalpha, suggesting a specific function for GM3. We were able to extend these in vitro observations to living animals using obese Zucker fa/fa rats and ob/ob mice, in which the GM3 synthase mRNA levels in the white adipose tissues are significantly higher than in their lean controls. In the DRMs from TNFalpha-treated 3T3-L1 adipocytes, GM3 levels were doubled, compared to results in normal adipocytes. Additionally, insulin receptor (IR) accumulations in the DRMs were diminished, while caveolin and flotillin levels were unchanged. GM3 depletion was able to counteract the TNFalpha-induced inhibition of IR accumulation into DRMs. Together, these findings provide compelling evidence that in insulin resistance the insulin metabolic signaling defect can be attributed to a loss of IRs in the microdomains due to an accumulation of GM3.     

The delicate balance between fat and muscle: adipokines in metabolic disease and musculoskeletal inflammation

Adipose tissue has evolved as a complex organ with functions far beyond the mere storage of energy. Chronic oversupply of calories, common to Western-style diets, frequently goes hand-in-hand with an altered secretion pattern of adipokines and elevated plasma free fatty acid levels, known to modulate insulin sensitivity in skeletal muscle. Intramyocellular accumulation of lipids directly attenuates insulin signaling within myocytes via distinct kinases. Obesity is also accompanied by an enhanced basal inflammatory tone, originating from adipocytes and adipose tissue-associated macrophages. In addition, adipocytes accumulate within the skeletal muscle and exert direct paracrine effects on muscle insulin sensitivity.     

A platelet-activating factor (PAF) receptor deficiency exacerbates diet-induced obesity but PAF/PAF receptor signaling does not contribute to the development of obesity-induced chronic inflammation

Platelet-activating factor (PAF) is a well-known phospholipid that mediates acute inflammatory responses. In the present study, we investigated whether PAF/PAF receptor signaling contributed to chronic inflammation in the white adipose tissue (WAT) of PAF receptor-knockout (PAFR-KO) mice. Body and epididymal WAT weights were higher in PAFR-KO mice fed a high-fat diet (HFD) than in wild-type (WT) mice. TNF-α mRNA expression levels in epididymal WAT and the infiltration of CD11c-positive macrophages into epididymal WAT, which led to chronic inflammation, were also elevated in HFD-fed PAFR-KO mice. HFD-fed PAFR-KO mice had higher levels of fasting serum glucose than HFD-fed WT mice as well as impaired glucose tolerance. Although PAF receptor signaling up-regulated the expression of TNF-α and lipopolysaccharide induced the expression of acyl-CoA:lysophosphatidylcholine acyltransferase 2 (LPCAT2) mRNA in bone marrow-derived macrophages, no significant differences were observed in the expression of LPCAT2 mRNA and PAF levels in epididymal WAT between HFD-fed mice and normal diet-fed mice. In addition to our previous finding in which energy expenditure in PAF receptor (PAFR)-deficient mice was low due to impaired brown adipose tissue function, the present study demonstrated that PAF/PAF receptor signaling up-regulated the expression of Ucp1 mRNA, which is essential for cellular thermogenesis, in 3T3-L1 adipocytes. We concluded that the marked accumulation of abdominal fat due to HFD feeding led to more severe chronic inflammation in WAT, which is associated with glucose metabolism disorders, in PAFR-KO mice than in WT mice, and PAF/PAF receptor signaling may regulate energy expenditure and adiposity.     

Tissue-specific glucocorticoid reactivating enzyme, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)--a promising drug target for the treatment of metabolic syndrome

Obesity is closely associated with the Metabolic Syndrome, which includes insulin resistance, glucose intolerance, dyslipidemia and hypertension. The best predictor of these morbidities is not the total body fat mass but the quantity of visceral (e.g. omental, mesenteric) fat. Glucocorticoids play a pivotal role in regulating fat metabolism, function and distribution. Indeed, patients with Cushing-s syndrome (a rare disease characterized by systemic glucocorticoid excess originating from the adrenal or pituitary tumors) or receiving glucocorticoid therapy develop reversible visceral fat obesity. The role of glucocorticoids in prevalent forms of human obesity, however, has remained obscure, because circulating glucocorticoid concentrations are not elevated in the majority of obese subjects. Glucocorticoid action on target tissue depends not only on circulating levels but also on intracellular concentration. Locally enhanced action of gluccorticoids in adipose tissue and skeletal muscle has been demonstrated in the Metabolic Syndrome. Evidence has accumulated that enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration, is commonly elevated in fat depots from obese individuals. This suggests a role for local glucocorticoid reactivation in obesity and the Metabolic Syndrome. 11beta-HSD1 knockout mice resist visceral fat accumulation and insulin resistance even on a high-fat diet. Furthermore, fat-specific 11beta-HSD1 transgenic mice, those have increased enzyme activity to a similar extent seen in obese humans, develop visceral obesity with insulin and leptin resistance, dyslipidemia and hypertension. In adipocytes, both antidiabetic PPARgamma agonists and LXRalpha agonists significantly reduce 11beta-HSD1 mRNA and enzyme activity, suggesting that suppression of 11beta-HSD1 in adipose tissue may be one of the mechanisms by which these drugs exert beneficial metabolic effects. Recently reported selective inhibitors of 11beta-HSD1 can ameliorate severe hyperglycemia in the genetically diabetic obese mice. In summary, 11beta-HSD1 is a promising pharmaceutical target for the treatment of the Metabolic Syndrome.     

Bilobalide abates inflammation,insulin resistance and secretion of angiogenic factors induced by hypoxia in 3T3-L1 adipocytes by controlling NF-κB and JNK activation

Obesity leads to inflammation and insulin resistance in adipose tissue. Hypoxia, observed in obese adipose tissue is suggested as a major cause of inflammation and insulin resistance in obesity. However, the role of hypoxia in adipose tissue during obesity and insulin resistance was not well established. Here we mainly explored the crosstalk between hypoxia induced inflammation, and insulin resistance and also secretion of angiogenic factors in 3T3-L1 adipocytes and possible reversal with bilobalide. Hypoxia for 24 h significantly (P ≤ 0.05) increased the secretion of MCP-1 (4.59 fold), leptin (2.96 fold) and reduced adiponectin secretion (2.93 fold). In addition, the mRNA level of resistin (6.8 fold) and TLR4 receptors (8.8 fold) was upregulated in hypoxic adipocytes. The release of inflammatory cytokines and expression of TLR4 receptors led to activation of JNK and NF-κB signalling. We further investigated the effects of JNK and NF-κB activation on insulin signalling receptors. The present study showed increased (P ≤ 0.05) serine 307 phosphorylation of IRS-1 (1.9 fold) and decreased expression of IRS-2 (0.53 fold) in hypoxic group showing hypoxia induced impairment in insulin signalling. Hypoxia significantly (P ≤ 0.05) increased basal glucose uptake (3.3 fold) as well as GLUT-1 expression in adipocytes indicating GLUT-1 mediated glucose uptake. Hypoxia for 24 h significantly increased (P ≤ 0.05) the expression of angiogenic factors. Bilobalide protected adipocytes from hypoxia induced inflammation and insulin resistance mainly by reducing inflammatory adipokine secretion, improving adiponectin secretion, reducing NF-κB/JNK activation, and inhibiting serine phosphorylation of IRS-1 receptors of insulin signalling pathway.     

Intraperitoneal Injection of Clodronate Liposomes Eliminates Visceral Adipose Macrophages and Blocks High-fat Diet-induced Weight Gain and Development of Insulin Resistance

Macrophage infiltration in adipose tissue is strongly correlated with obesity. The exact role of macrophage in the development of obesity, however, has not been fully understood. In this study, using intraperitoneal injection of clodronate liposomes, we tissue-specifically depleted visceral adipose tissue macrophages (VATMs) and explored their roles in initiation and progression of obesity. Two sets of experiments were conducted, using mice on a high-fat diet as the animal model. Mice were injected with clodronate liposomes at the beginning of high-fat diet feeding to investigate the role of VATMs in the initiation of obesity. Treatment starting on week 5 was designed to explore the function of VATMs in the progression of weight gain. The results show that intraperitoneal injection of clodronate liposomes effectively depleted VATMs, which blocked high-fat diet-induced weight gain, fat accumulation, insulin resistance, and hepatic steatosis. Similarly, clodronate liposomes suppressed progression of weight gain in mice after being fed with a high-fat diet for 4 weeks and improved insulin sensitivity. Gene expression analysis showed that depletion of VATMs was associated with downregulation of the expression of genes involved in lipogenesis and gluconeogenesis including acc1, fas, scd1, and pepck, decreased expression of genes involved in chronic inflammation including mcp1 and tnfα, and suppressed expression of macrophage specific marker genes of f4/80 and cd11c in adipose tissue. Depletion of VATMs was associated with prevention of the formation of crown-like structures in white adipose tissue and the maintenance of a low level of blood TNF-α. Collectively, these data demonstrate that VATMs appeared to play a crucial role in the development of obesity and obesity-associated diseases and suggest that adipose tissue macrophages could be regarded as a potential target for drug development in prevention and therapy of obesity and obesity-associated complications.     

In silico and in vivo analysis to identify the antidiabetic activity of beta sitosterol in adipose tissue of high fat diet and sucrose induced type-2 diabetic experimental rats

Adipose tissue is the primary site of storage for excess energy as triglyceride and it helps in synthesizing a number of biologically active compounds that regulate metabolic homeostasis. Consumption of high dietary fat increases stored fat mass and is considered as a main risk factor for metabolic diseases. Beta-sitosterol (β-sitosterol) is a plant sterol. It has the similar chemical structure like cholesterol. Clinical and experimental studies have shown that β-sitosterol has anti-diabetic, hypolipidemic, anti-cancer, anti-arthritic, and hepatoprotective role. However, effect of β-sitosterol on insulin signaling molecules and glucose oxidation has not been explored. Hence in the present study we aimed to discover the protective role of β-sitosterol on the expression of insulin signaling molecules in the adipose tissue of high-fat diet and sucrose-induced type-2 diabetic experimental rats. Effect dose of β-sitosterol (20?mg/kg b.wt, orally for 30?days) was given to high fat diet and sucrose-induced type-2 diabetic rats to study its anti-diabetic activity. Results of the study showed that the treatment with β-sitosterol to diabetes-induced rats normalized the altered levels of blood glucose, serum insulin and testosterone, lipid profile, oxidative stress markers, antioxidant enzymes, insulin receptor (IR), and glucose transporter 4 (GLUT4) proteins. Our present findings indicate that β-sitosterol improves glycemic control through activation of IR and GLUT4 in the adipose tissue of high fat and sucrose-induced type-2 diabetic rats. Insilico analysis also coincides with invivo results. Hence it is very clear that β-sitosterol can act as potent antidiabetic agent.     

吡格列酮改善氧化应激导致的脂肪细胞胰岛素抵抗

目的:观察吡格列酮对氧化应激导致的脂肪细胞胰岛素抵抗的作用,初步探讨其机制。方法:葡萄糖氧化酶(GO)作用培养于高糖DMEM的3T3-L1细胞产生H2O212小时后观察胰岛素刺激的葡萄糖摄取(ISGU)和胰岛素信号通路主要分子的活化状态以及吡格列酮的影响。结果:GO导致的氧化应激抑制ISGU和IRS-1酪氨酸及PKB磷酸化,其机制可能与氧化应激导致IRS-1丝氨酸307磷酸化有关;氧化应激的作用可被吡格列酮部分逆转。结论:吡格列酮可以减轻氧化应激导致的脂肪细胞胰岛素抵抗,改善胰岛素信号传导。     

吡格列酮对高脂喂养大鼠骨骼肌组织脂质异位沉积的影响

目的:观察吡格列酮(Pio)对高脂喂养大鼠骨骼肌组织脂质异位沉积的影响。方法:30只Wistar大鼠平均分为对照组、胰岛素抵抗组和吡格列酮干预组,对照组给予基础饲料,其余2组均给予高脂饲料喂养,其中吡格列酮干预组同时给予吡格列酮20 mg·kg^-1·d^-1灌胃,各组均喂养16周后检测各组大鼠血游离脂肪酸(FFA)水平及骨骼肌组织中三酰甘油(TG)含量,同时应用蛋白免疫印迹法检测骨骼肌组织一磷酸腺苷活化蛋白激酶α(AMPKα)磷酸化水平。结果:与对照组比较,胰岛素抵抗组大鼠胰岛素敏感性显著降低,血FFA水平及骨骼肌组织TG含量增高,骨骼肌组织中AMPKα磷酸化水平降至对照组水平的52.9%;与胰岛素抵抗组比较,吡格列酮干预组大鼠胰岛素敏感性明显提高,血FFA水平及骨骼肌组织TG含量显著下降,骨骼肌组织中AMPKα磷酸化水平显著提高至对照组的81.3%。但是与对照组比较,吡格列酮干预组大鼠血FFA水平及骨骼肌组织TG含量仍然较高,而且胰岛素敏感性及骨骼肌组织中AMPKα磷酸化水平仍然显著降低。结论:高脂饮食诱导胰岛素抵抗,吡格列酮干预可以通过降低血FFA水平及减轻骨骼肌组织脂质异位沉积改善其胰岛素抵抗。     

2型糖尿病患者抗炎治疗前后相关指标分析

目的探讨2型糖尿病（T2DM）患者血清脂联素（APN）与炎性因子的相关性,并观察抗炎药物对糖尿病患者的疗效。方法将2型糖尿病患者分为T2DM合并血管病变组（A组）53例,T2DM无血管病变组（B组）47例,以健康人30例为对照组。分别检测抗炎治疗前后各组胰岛素、糖化血红蛋白（HbAlc）、血脂（1ipids）、游离脂肪酸（FFA）、C-反应蛋白（CRP）、APN、瘦素（Leptin）及肿瘤坏死因子（TNF-α）、胰岛素敏感性指数（ISI）及胰岛素抵抗指数（IR）等。结果ISI、IR、FFA、CRP、APN、Leptin、TNF-α含量均高于对照组（均P〈0．05）;抗炎治疗后明显下降（均P〈0．05）;APN平与HbAlc、HOMA-IR、CRP及TNF—α呈显著负相关（均P〈0．05）。结论APN是T2DM和动脉粥样硬化的保护性因子,抗炎治疗可能改善T2DM的预后。     

基于TNF-α和FABP4蛋白探究长期服用奥氮平导致胰岛素抵抗的作用机制

目的：探究在长期服用奥氮平诱导的胰岛素抵抗过程中，TNF-α和FABP4的相互作用。方法：选择SD大鼠连续灌胃给予奥氮平8周，建立奥氮平诱导胰岛素抵抗的大鼠模型，期间分别对大鼠体质量、空腹血糖（FBG）、空腹胰岛素（Fins）和胰岛素抵抗指数（HOMA-IR）进行测定比较；ELISA测定大鼠血清和白色脂肪中的TNF-α表达量；通过Western Blot对3T3-L1细胞模型中的研究蛋白（FABP4和GLUT4）进行分析比较。结果：与对照组相比，长期服用奥氮平诱导胰岛素抵抗的大鼠血清和白色脂肪内TNF-α表达量显著升高（P<0.05），且在3T3-L1脂肪细胞模型中，随着TNF-α浓度增加，FABP4的表达量显著上升（P<0.05），GLUT4的上膜量显著降低（P<0.05）。结论：长期服用奥氮平可能引起机体产生炎症反应，激活TNF-α的表达，进而上调FABP4蛋白，最终降低GLUT4上膜量，导致胰岛素抵抗的发生。     

牛磺酸对胰岛素抵抗大鼠脂肪组织PAI-1mRNA表达的影响

目的 :观察牛磺酸对胰岛素抵抗大鼠的治疗作用。方法 :选择 SD雄性大鼠 ,按体重随机分为正常组和造模组 ,造模组大鼠饲以特殊高脂饲料 30 d,造成胰岛素抵抗动物模型 ;经牛磺酸治疗 30 d后 ,取血检测血糖、胰岛素等指标 ,计算胰岛素抵抗敏感指数。运用 RT- PCR技术测定大网膜脂肪组织 PAI- 1m RNA的表达。结果 :采用特殊高脂饲料可以成功诱导胰岛素抵抗动物模型 ;牛磺酸可提高胰岛素抵抗大鼠胰岛素敏感指数 (P<0 .0 5 ) ,下调脂肪组织PAI- 1m RNA的表达。结论 :牛磺酸具有提高胰岛素敏感性作用 ,以及阻断 PAI- 1m RNA的过度表达的综合效应。     

Effects of bofu-tsusho-san, a traditional Chinese medicine, on body fat accumulation in fructose-loaded rats

The effects of Bofu-tsusho-san (BOF), a traditional Chinese medicine, on fructose-induced hypertriglyceridemia and body fat accumulation were investigated in female SD rats. Rats were allowed to drink ad libitum 25% (w/w) fructose solution for 6 weeks. BOF was administered to the rats as an experimental diet containing 1.5% or 4.5% (w/w) of BOF during the fructose-loading period. BOF suppressed body weight gain and prevented the elevation of serum triglyceride levels and body fat accumulation in fructose-loaded rats without affecting food and fructose intake. Furthermore, BOF prevented the increase of triglyceride content in the liver and the reduction of mitochondrial cytochome c oxidase activity in the brown adipose tissue induced by fructose. From these results, it has been suggested that BOF has a preventive effect against the body fat accumulation caused by excess intake of sugar or other fructose-containing foods. The inhibition of triglyceride synthesis in the liver, and the enhancement of lipolysis in adipocytes and of thermogenesis in brown adipose tissue have been presumed as the mechanisms of action of BOF.     

Depot-specific alterations to insulin signaling in mesenteric adipose tissue during intestinal inflammatory response

Current knowledge suggests that adipose tissue is an active organ, participating in intestinal and mesenteric disease. Additionally, adipose tissue surrounds the lymph nodes and has special properties, acting as a paracrine regulator of adjacent lymphoid tissues. These adipose tissue depots can express and secrete numerous cytokines, known as adipocytokines, which then modify the action of insulin in adipose tissue itself. Using a well-accepted model of intestinal inflammation, we studied insulin signaling in mesenteric adipose tissue (MAT) and in perinodal mesenteric adipose tissue (PAT). Our results showed that the action of insulin is modified during the intestinal inflammatory response in these adipose tissue depots. MAT became resistant to insulin signaling, as evaluated by the IRS/AKT pathway, in the inflammation. This resistant status was associated with high JNK activity and the presence of infiltrating macrophages. Conversely, the adipose tissue that involves the mesenteric lymph nodes acquired greater sensitivity to insulin signaling via IRS/AKT, probably via up-regulation of IRS during experimental colitis. We demonstrated experimentally the existence of site-specific adaptive alterations in two mesenteric adipose tissue depots to the intestinal inflammatory response, probably resulting in alterations in free fatty acids and other secretory products supplied by the adjacent tissues that could act as inflammatory modulator substances.     

Adipose tissue as a regulator of energy balance

Adipose tissue plays an active role in energy balance because it is not only a lipid storing and mobilizing tissue but consists of functionally specialized tissues able to produce heat (in brown adipose tissue) and to produce or release a vast number of so called adipokines or adipocytokines. These consist of polypeptides but also non-protein factors and are metabolically active molecules belonging to different functional categories like immunity (complement factors, haptoglobin), endocrine function (leptin, sex steroids, various growth factors), metabolic function (fatty acids, adiponectin, resistin), and cardiovascular function (angiotensinogen, PAI-1). Recent advances using genomic and proteomic approaches have identified numerous new adipocyte secreted factors whose function remain to be established. Too little as well as too much adipose tissue leads to metabolic disturbances like insulin resistance. Visceral obesity is especially strongly correlated with the development of diabetes, hypertension and cardio-vascular disease. Thermogenesis in brown adipose tissue is a means to dissipate excess energy, but in adult humans brown fat is very scarce and probably not functional. However, human white adipose tissue contains mesenchymal stem cells, and if these could be stimulated to differentiate into brown adipocytes, increased energy expenditure in white fat could help to shift energy balance towards a more negative state.