FAT/CD36在高脂喂养小鼠脂肪组织炎症中的作用

目的:探讨脂肪酸转运酶/白细胞分化抗原36(fatty acid translocase/CD36,FAT/CD36)在高脂饮食诱导的小鼠脂肪组织炎症中的作用。方法:将6周龄雄性C57BL/6J小鼠分别随机分为普通饮食组和高脂饮食组,喂养14周后,ELISA测定血清游离脂肪酸(FFA)含量,应用荧光实时定量PCR和Western blotting检测脂肪组织中FAT/CD36及炎症/趋化因子(IL-1β、IL-6、TNF-α、MCP-1、MIP-1)mRNA和蛋白的表达,免疫组织化学染色检测脂肪组织巨噬细胞浸润,比较高脂喂养14周的野生型小鼠和CD36基因敲除小鼠的脂肪组织炎症反应情况。结果:与普通饮食组相比,高脂饮食能增强C57BL/6J小鼠脂肪组织的FAT/CD36及炎症/趋化因子的表达,促进巨噬细胞在脂肪组织的浸润。与高脂饮食喂养的野生型小鼠相比,CD36基因敲除小鼠的脂肪组织炎症因子、趋化因子表达明显降低,脂肪组织巨噬细胞浸润减少。结论:高脂饮食通过上调脂肪组织FAT/CD36的表达激活了脂肪组织炎症。     

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：     

高脂饲养C57BL/6J小鼠肾周脂肪组织炎性反应的评估

目的评估高脂饲养C57BL/6J小鼠肾周脂肪组织炎性反应。方法将小鼠随机分为对照组(control组,n=6)和高脂饲养组(HFD组,n=6)。用RT-qPCR检测肾周脂肪组织中TNF-α、CD11c、IL-1β、IL-10、TGF-β1、CD206等mRNA的表达;免疫组织化学法检测肾周脂肪组织及肾实质F4/80、CD68、LCA的水平。结果与对照组比较,HFD组小鼠肾周脂肪组织TNF-α、IL-1β等mRNA相对含量升高(P0.05);HFD组的肾周脂肪巨噬细胞标志物F4/80,CD68及炎细胞广谱标志物LCA的表达均呈高表达(P0.05)。结论高脂饲养的C57BL/6J小鼠肾周脂肪组织确实存在明显的炎性反应。     

褪黑素受体激动剂改善高糖高脂喂养大鼠脂联素敏感性

目的 观察褪黑素受体激动剂(NEU-P11)对高糖高脂饲养大鼠脂联素敏感性的影响.方法 将30 只SD大鼠随机分为对照组(CD组),高糖高脂组(HFSD组),褪黑素组(Mel组),褪黑素受体激动剂组(NEU-P11组).CD组饲以正常饲料;其余3组饲以高糖高脂饲料.6个月后,给药治疗2个月.治疗期间,Mel组每天注射Mel(4 mg/kg);NEU-P11组每天注射NEU-P11(10 mg/kg);CD组以及HFSD组注射生理盐水(5 ml/kg).测定糖脂代谢指标并做口服葡萄糖耐量实验(oral glucose tolerant test,OGTT),Western印迹检测脂联素(adiponectin,APN)在脂肪组织及脂联素受体(AdipoR)在骨骼肌组织中的表达变化.结果 高糖高脂饮食可诱导SD大鼠产生胰岛素抵抗,脂联素表达增加.Neu-P11治疗后,胰岛素敏感性增强,脂联素表达降低至正常水平.结论 Neu-P11能提高胰岛素敏感性,改善脂联素抵抗.     

肥胖小鼠脂肪组织中炎症因子的表达

目的 探讨肥胖对小鼠脂肪中炎症因子分泌的影响及其作用的分子机制。方法 随机选取20只Lepob/ob肥胖小鼠作为研究对象,同窝野生型C57BL/6 J小鼠作为对照组。测定小鼠体重、脂肪重量、血糖、葡萄糖耐量和胰岛素耐量;HE染色观察白色和褐色脂肪细胞的状态,并对脂肪细胞直径进行统计学分析;Western blotting检测诱导型一氧化氮合酶(iNOS)、核因子κB（NF-κB）、蛋白激酶B（Akt）和p-Akt的蛋白表达;Real-time PCR分析白色和褐色脂肪中CC-趋化因子配体2(CCL2)、CD44、集落刺激因子2(CSF2)、胶质纤维酸性蛋白（GFAP）、Iba1、白细胞介素(IL)-1α、IL-6、IL-7、JUN和S100β mRNA的表达。结果 与对照组相比,Lepob/ob 小鼠的体重随年龄的增长而显著增加（P<0.001）,白色脂肪重量、皮下脂肪重量及血糖显著升高（P<0.01,P<0.01,P<0.01）,葡萄糖耐量较低（P<0.001）并产生胰岛素抵抗（P<0.001）;脂肪细胞直径显著增大,且各个脂肪组织均有巨噬细胞浸润灶出现;脂肪细胞内Janus蛋白酪氨酸激酶2(JAK2)、p-JAK2、iNOS、NF-κB、Akt和p-Akt蛋白表达均显著升高（P<0.05）;CCL2、CD44、IL-1α、IL-6、IL-7、JUN和S100β mRNA表达均显著升高。 结论 肥胖诱导小鼠脂肪组织中炎症因子显著表达,促使细胞分泌传导紊乱,导致炎症级联发生。     

Metrnl在肥胖小鼠模型中的表达

目的:探讨肥胖对小鼠各组织中Metrnl表达的影响。方法:高脂饮食4个月诱导小鼠肥胖,实时定量PCR与免疫组织化学法检测正常饮食与高脂饮食小鼠肝、骨骼肌、肾、结肠及脂肪组织中Metrnl mRNA与蛋白的表达。结果:高脂饮食增加了小鼠的体质量和白色脂肪量。同时,高脂饮食显著增加了白色脂肪组织Metrnl mRNA与蛋白的水平,但未增加肝、骨骼肌、肾、结肠组织中Metrnl的表达。结论:肥胖特异性增加脂肪组织中Metrnl的表达,从而形成"肥胖-脂肪组织上调Metrnl表达-代谢改善"的反馈调节通路。     

CYP450表氧化酶/EET代谢途径通过HIF-1α减轻肥胖小鼠脂肪炎症

目的:比较细胞色素P450(CYP450)表氧化酶在肥胖小鼠与正常小鼠内脏脂肪组织中的表达差异,观察外源性环氧二十碳三烯酸(EET)对肥胖小鼠胰岛素抵抗、炎症及血管再生的影响。方法:以C57BL/6Cnc小鼠为研究对象,经高脂饮食建立小鼠肥胖模型。成模后,将肥胖小鼠随机分为肥胖组(n=10)、EET组(n=10)和EET拮抗剂14,15-环氧二十碳-5(Z)-烯酸(EEZE)组(n=10),分别腹腔注射生理盐水、11,12-EET和14,15-EEZE。普通饮食饲养的非肥胖C57BL/6Cnc小鼠作为正常对照组(n=10)。Western blot检测小鼠内脏脂肪组织CYP2J2(一种CYP450表氧化酶)及低氧诱导因子1α(HIF-1α)的蛋白表达水平;ELISA检测血清胰岛素及炎症因子水平;免疫组化检测内脏脂肪组织毛细血管密度。结果:与正常小鼠相比,肥胖小鼠胰岛素抵抗指数上升,内脏脂肪CYP2J2表达降低,HIF-1α表达升高,血清中炎症因子水平增高,内脏脂肪中血管样组织减少(均P0.05)。外源性11,12-EET可以显著降低肥胖小鼠胰岛素抵抗指数、内脏脂肪组织中HIF-1α表达和血清炎症因子水平,促进内脏脂肪血管样组织生成(均P0.05)。结论:EET可减轻肥胖小鼠胰岛素抵抗、脂肪组织缺氧和炎症,并促进血管生成。     

胰岛素抵抗小鼠脂肪组织肿瘤坏死因子α和脂联素mRNA表达与有氧运动的影响

背景：有研究表明有氧运动可通过调节脂肪组织过氧化物酶体激活物增殖受体γ及其相关脂肪因子进而影响胰岛素敏感性,但其影响结果及作用机制至今少有报道。 目的：观察有氧运动后,胰岛素抵抗C57BL/6小鼠脂肪组织过氧化物酶体激活物增殖受体γ、肿瘤坏死因子α和脂联素 mRNA及蛋白表达水平的变化,分析有氧运动对胰岛素抵抗小鼠影响的作用机制。 方法：C57BL /6 小鼠经高脂饮食喂养10周后建立胰岛素抵抗动物模型,建模后将小鼠随机分为安静组与运动组。运动组进行为期6周,75% VO2max强度跑台运动;安静组同等条件下饲养不运动。使用RT-PCR 和Western blot法检测两组脂肪组织过氧化物酶体激活物增殖受体γ,脂联素、肿瘤坏死因子α mRNA和蛋白表达。 结果与结论：6周有氧跑台运动对小鼠脂肪组织过氧化物酶体激活物增殖受体γ表达差异无显著性意义(P > 0.05),但可显著增加小鼠脂肪组织脂联素的表达(P< 0.01),降低肿瘤坏死因子α的表达(P < 0.05);并且可显著降低血液中三酰甘油、游离脂肪酸水平(P < 0.05, P < 0.01)。结果提示有氧运动可能通过调节过氧化物酶体激活物增殖受体γ相关脂肪因子-脂联素和肿瘤坏死因子α的表达来间接调节脂肪组织对胰岛素的敏感性。有氧运动可以显著增加机体组织对胰岛素的敏感性,从而改善C57BL/6 小鼠胰岛素抵抗的症状。     

TLR4抑制剂TAK-242对高脂饮食诱导的小鼠胰岛素抵抗的干预作用

目的建立高脂饮食诱导的胰岛素抵抗小鼠模型,探讨干预Toll样受体4(Toll-like receptor 4,TLR4)对高脂饮食诱导的小鼠胰岛素抵抗状态的影响。方法首先建立高脂饮食诱导的胰岛素抵抗小鼠模型。选取出生21 d的雄性C57BL/6小鼠36只,随机分为2组,正常对照组12只,以普通基础饲料喂养(low fat diet,LFD),高脂饮食实验组24只,给予高脂饲料喂养(high fat diet,HFD)。待2组小鼠体质量出现显著差异时,进行葡萄糖耐量实验(glucose tolerance test,GTT)和胰岛素耐量实验(insulin tolerance test,ITT)观察小鼠胰岛素抵抗的发生。小鼠胰岛素抵抗模型建立后,观察TLR4抑制剂TAK-242对小鼠胰岛素抵抗状态的作用。LFD组小鼠继续以基础饲料喂养(即作LFD对照组);HFD组小鼠随机分为2组,每组12只小鼠,均继续以高脂饲料喂养,其中一组HFD小鼠腹腔注射TLR4抑制剂TAK-242,以0.5 mg TAK-242/kg体质量的计量给予,每周2次(即给予TAK-242的高脂饮食实验组,HFD-T组);另一组HFD小鼠作为单纯高脂饮食的胰岛素抵抗空白对照组(HFD-C组),只给予等体积的溶媒-二甲基亚砜(DMSO)。给予小鼠TLR4抑制剂5个月,进行GTT和ITT后,处死小鼠。采用EDTA-K2抗凝管收集血液标本,立即分离外周血单核细胞(peripheral blood mononuclear cell,PBMC)和血浆。应用Western blot技术检测PBMC TLR4蛋白表达水平。采用全自动生化分析仪测定血浆葡萄糖(GLU)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、丙氨酸氨基转移酶(ALT)的水平。结果在小鼠胰岛素抵抗模型建立期间,与对照组相比,高脂饮食组小鼠体质量增长较快,喂养至第20周体质量出现显著差异(P0.05);持续高脂饮食7个月,GTT和ITT结果显示,高脂饮食组小鼠对糖的调节能力受损、对胰岛素的降糖作用减低,说明高脂饮食诱导小鼠胰岛素抵抗成功。出现胰岛素抵抗的小鼠,在给予TLR4抑制剂TAK-242 5个月后,对葡萄糖的调节能力和对胰岛素的敏感性均有所改善。血浆生化指标结果显示,与对照组比较,单纯高脂组和给予TAK-242的高脂饮食干预组小鼠血浆TG、TC、LDL-C浓度均显著升高(P0.05),GLU、HDL-C、ALT水平均有升高趋势,但无统计学意义(P0.05)。单纯高脂组和TAK-242干预组比较,血浆GLU、TG、TC、LDL-C、HDL-C、ALT水平在2组之间不存在显著性差异(P0.05)。Western blot实验结果发现,正常对照组小鼠PBMC未见TLR4蛋白表达,单纯高脂饮食组小鼠PBMC有高水平的TLR4蛋白表达,给予TAK-242的高脂饮食小鼠PBMC TLR4蛋白虽有表达,但表达量明显低于单纯高脂饮食组小鼠,结果提示TAK-242部分抑制了高脂饮食喂养小鼠PBMC TLR4蛋白的表达。结论高脂饮食成功诱导了小鼠产生胰岛素抵抗,抑制TLR4蛋白的表达可以改善小鼠胰岛素抵抗状态。该研究结果丰富了胰岛素抵抗发生的机制,为进一步深入研究TLR4及其信号通路在胰岛素抵抗中的作用提供了实验依据。     

小檗碱改善高脂饮食大鼠的胰岛素抵抗

目的:观察小檗碱是否能改善高脂饮食诱导的胰岛素抵抗,以探讨小檗碱干预糖耐量受损(IGT)的可能性。方法:8周龄雄性SD大鼠29只,分为正常组(NC,n=9)和高脂组(HF,n=20)。高脂饲料喂养14周后高脂组分为二组,10只大鼠继续喂养高脂饮食,另一小檗碱组(HF B,n=10)每天灌胃小檗碱150mg/kg体重,治疗6周后进行口服葡萄糖耐量试验和胰岛素耐量试验(ITT),评估小檗碱对胰岛素敏感性的影响。结果:HF组大鼠体重、肝重和附睾脂肪重量均明显高于HF B和NC组(均P<0.01),HF B组空腹血糖和葡萄糖负荷后2h血糖明显低于HF组(分别为5.70±0.52mmol/Lvs6.66±0.51mmol/L和7.88±0.46mmol/Lvs8.85±1.01mmol/L),空腹和葡萄糖负荷后2h胰岛素HF B组也显著低于HF组(分别为0.63±0.25ng/mlvs1.64±0.68ng/ml和1.20±0.21ng/mlvs3.60±0.36ng/ml)。各时间点血糖和胰岛素HF组均显著高于NC组(均P<0.01)。Homa胰岛素抵抗指数HF组明显高于HF B组(P<0.01)。ITT腹腔注射胰岛素后各时间点血糖下降幅度HF B组均高于HF组,15min时HF B组血糖下降23%,而HF组仅下降7%。结论:长期高脂饮食可导致大鼠胰岛素抵抗,小檗碱明显降低高脂大鼠的高胰岛素血症,改善胰岛素抵抗,因此适合于IGT的干预。     

Effects of a High-Fat Diet on Adipose Tissue CD8+ T Cells in Young <Emphasis Type="Italic">vs</Emphasis>. Adult Mice

T cells are involved in chronic inflammation of adipose tissue in obese conditions. However, the impact of age on the adipose T cells remains unknown. In this study, we investigated T cells in the white adipose tissue of young and adult mice. Obesity was induced in the mice using a high-fat diet (HFD) for 14 weeks. The young mice were fed an HFD at 3 weeks old, and adult mice were fed the HFD at 12 weeks old. Relative to adult mice, the young mice gained less fat and exhibited better glucose tolerance. Their adipose tissue contained more CD8+ T cells and higher levels of pro-inflammatory cytokines. Young mice showed a larger increase in CD4+ T cells. The young and adult mice showed similar insulin tolerance. HFD reduced the colon muscle layer, which was more obvious in the young mice. These data suggested that young and adult mice exhibit different responses to an HFD in terms of adipose tissue, glucose tolerance, and the colon muscle layer. The increase in CD8+ T cells and CD4+ T cells, together with higher levels of pro-inflammatory cytokines, suggested elevated inflammation in the presence of less fat gain in the young mice, which was unexpected. The significance of this inflammation remains unknown. We propose that inflammation might inhibit energy storage in the adipose tissue to provide more energy to the lean body mass in favor of growth in the young mice. The present study provides another example of the beneficial effect of inflammation in physiological conditions.     

High-Carbohydrate Diet Selectively Induces Tumor Necrosis Factor-α Production in Mice Liver

Obesity may represent a state of chronic low-grade inflammation associated with infiltration of adipose tissue by inflammatory cells. Tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1/JE), two important inflammatory cytokines, have been shown to be regulated according to changes in body adiposity. In this study on Swiss mice, we compared the influences of long-term high-carbohydrate (HC) or high-fat (HF) diet on adiposity, glucose tolerance, and secretion of TNF-α and MCP-1/JE by adipose tissue and liver. For 8 weeks, male Swiss mice (7–8 weeks) were fed either standard laboratory rodent diet (control group), HC diet (64% carbohydrate, 19% protein, and 11% fat), or HF diet (45% carbohydrate, 17% protein, and 38% fat), with the latter two diets having no fiber. Oral glucose tolerance test, triacylglycerol (TAG) plasma concentration, and systemic or tissue levels of the two proinflammatory cytokines were determined. Body weight increased by approximately 20% in mice fed the experimental diets compared with mice fed the control diet. Systemically, the hypercaloric diets induced hyperglycemia with impairment in glucose tolerance, elevated circulating TAG levels, and increased plasma concentrations of TNF-α and MCP-1/JE. In the target organs (adipose tissue and liver), both diets increased MCP-1/JE levels. However, the HC diet, but not the HF diet, was able to increase TNF-α concentration in the liver. These results have shown that the nature of nutrients influences the type of proinflammatory cytokines in target organs and may contribute to the comorbidities of obesity.     

高脂饮食诱导肥胖小鼠表达卵泡抑素样蛋白1与脂肪组织炎症和棕色脂肪的功能

目的 探讨卵泡抑素样蛋白1（FSTL1）在高脂饮食诱导的肥胖小鼠脂肪炎症中的作用,以及对棕色脂肪功能的影响。 方法 6周龄C57BL/6 J小鼠分为两组,每组8只,给予12周正常饮食（RD）和高脂饮食（HFD）饲养,每周称量小鼠体重,记录小鼠摄食量;12周后,进行糖耐量和胰岛素耐量的检测并取材,称量小鼠的皮下白色脂肪、肾周白色脂肪、附睾白色脂肪和棕色脂肪的重量;HE染色观察小鼠白色脂肪中的冠状结构（CLS）及小鼠棕色脂肪组织变化,RT-PCR分析小鼠附睾白色脂肪炎症因子、肿瘤坏死因子α（TNF-α)、白细胞介素6（IL-6）和白细胞介素10（IL-10）的表达,以及FSTL1的表达;Western blotting检测棕色脂肪解耦联蛋白1（UCP1）与FSTL1蛋白的表达。 结果 与RD小鼠相比,HFD组小鼠的体重增加,摄食量减少,不同部位脂肪重量显著增加,葡萄糖耐受能力显著降低,胰岛素敏感性显著下降,附睾白色脂肪观察到炎症反应CLS且附睾白色脂肪中炎症因子TNF-α、IL-6及IL-10表达显著增高, FSTL1表达亦显著增加。Western blotting结果显示,HFD小鼠的棕色脂肪组织中UCP1与FSTL1表达水平均显著性高于RD组。 结论 在高脂饮食诱导的肥胖小鼠中,FSTL1的表达可能与脂肪炎症因子的分泌增加及棕色脂肪的功能有一定相关性。     

mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function

Genetic- and diet-induced obesity and insulin resistance are associated with an increase in mechanistic target of rapamycin complex (mTORC) 1 activity in adipose tissue. We investigated herein the effects of pharmacological mTORC1 inhibition in the development of adipose tissue inflammation induced by high-fat diet (HFD) feeding, as well as in the polarization, metabolism and function of bone marrow-derived macrophages (BMDM). For this, C57BL/6J mice fed with a standard chow diet or a HFD (60% of calories from fat) and treated with either vehicle (0.1% Me₂SO, 0.2% methylcellulose) or rapamycin (2 mg/ kg/ day, gavage) during 30 days were evaluated for body weight, adiposity, glucose tolerance and adipose tissue inflammation. Although rapamycin did not affect the increase in body weight and adiposity, it exacerbated the glucose intolerance and adipose tissue inflammation induced by HFD feeding, as evidenced by the increased adipose tissue percentage of M1 macrophages, naive and activated cytotoxic T lymphocytes, and mRNA levels of proinflammatory molecules, such as TNF-α, IL-6 and MCP-1. In BMDM in vitro, pharmacological mTORC1 inhibition induced phosphorylation of NFκB p65 and spontaneous polarization of macrophages to a proinflammatory M1 profile, while it impaired M2 polarization induced by IL-4 + IL-13, glycolysis and phagocytosis. Altogether, these findings indicate that mTORC1 activity is an important determinant of adipose tissue inflammatory profile and macrophage plasticity, metabolism and function.     

脂联素抑制脂肪组织MHC Ⅱ表达及对糖脂代谢的影响

目的:探讨脂联素是否通过影响脂肪组织主要组织相容性复合物Ⅱ类(MHCⅡ)的表达调节糖脂代谢。方法:脂联素基因敲除小鼠(KO)和C57BL/6小鼠(WT)分别给予高脂饲料或普通饲料,24周后,测量小鼠体重、空腹血糖(FBG)、空腹胰岛素(FINS)、稳态胰岛素评价指数(HOMA-IR)、血清甘油三酯(TG)、血清总胆固醇(TC)、血清低密度脂蛋白胆固醇(LDL-C)和血清高密度脂蛋白胆固醇(HDL-C);行肝脏组织病理形态学评价;检测脂肪组织MHCⅡ反式激活因子(CIITA)、小鼠MHCⅡ抗原Eβ(H2-Eb1)、MHCⅡ恒定链(CD74)mRNA及MHCⅡ相关蛋白质表达水平。用siRNA沉默3T3-L1脂肪细胞中MHCⅡ的表达及用过表达载体升高3T3-L1脂肪细胞中的脂联素和(或)MHCⅡ的表达,检测脂联素对MHCⅡ蛋白水平的影响。结果:高脂饲料或普通饲料喂养的KO小鼠体重、FBG、FINS、HOMA-IR、TC、TG、LDL-C、肝脂肪变性、脂肪组织中CIITA、H2-Eb1、CD74 mRNA和MHCⅡ蛋白表达水平均高于WT小鼠。在脂肪细胞中,抑制脂联素能够在一定程度上逆转siRNA干扰所引起的MHCⅡ表达降低,过表达脂联素后脂肪细胞中MHCⅡ的表达降低。结论:脂联素可以通过抑制脂肪组织中MHCⅡ的表达改善糖脂代谢。     

Intermittent Hypoxia Increases Insulin Resistance in Genetically Obese Mice

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J− Lep ^ob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 ± 11 mg dl⁻¹ on day 0 to 138 ± 10 mg dl⁻¹ on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 ± 0.3 vs. 1.7 ± 0.2 ng ml⁻¹, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 ± 136 % (   P < 0.01  ) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 ± 1.1 ng ml⁻¹ at baseline to 9.8 ± 1.8 ng ml⁻¹ at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.     

Vaspin and insulin resistance

We have identified the vaspin gene(serpina12), which is up-regulated in visceral white adipose tissues (WATs) of Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model of abdominal obesity and type 2 diabetes. Vaspin mRNA was barely detectable at 6 weeks of age, but was abundantly and exclusively expressed in visceral WATs at 30 weeks of age, when OLETF rats reach their peak body weight. However, vaspin mRNA decreased with worsening of diabetes and body weight loss. Vaspin mRNA increased with administration of thiazolidinediones, i.e. pioglitazone. Administration of recombinant vaspin into high fat high sucrose (HFHS) chow-induced obese ICR mice improved glucose tolerance and insulin sensitivity. Vaspin may be the compensatory molecule in the pathogenesis of metabolic syndrome and vaspin recombinant protein or vaspin-mimicking agents such as vaspin analogues, antibodies or small molecule agents would link to drug discovery and development.