MyD88在特定细胞型中对肥胖相关炎症疾病进展的作用
|
摘要
实验背景：低浓度的全身性炎症反应在肥胖相关炎症疾病如胰岛素抵抗及主动脉粥样硬化病变发展过程中起关键作用,并且与代谢综合征的发生呈相关性。高脂肪饮食(HFD)能影响肠道通透性,引发全身性炎症刺激因子的聚集,这些刺激因子包括了白介素-1受体(IL-1R)/toll样受体(TLRs)的内源性与外源性配基。并且已有既往研究证实了IL-1R/TLRs信号通路在高脂饮食致全身性炎症反应及肥胖致炎症疾病发展中均起着关键作用。
实验目的：本研究中,我们旨在探索TLR-MyD88(髓样分化因子88,myeloid differentiation factor88, IL-1R/TLRs主要衔接分子)信号通路是如何在不同细胞类型中协调性地参与HFD诱导的全身性炎症反应及代谢性炎症疾病的起始阶段。
实验方法：我们应用Cre-LoxP基因敲除技术得到内皮细胞特异性MyD88基因敲除小鼠(MyD88EC-KO)及骨髓/巨噬细胞特异性MyD88基因敲除小鼠(MyD88MC-KO).我们又将MyD88EC-KO小鼠与MyD88MC-Ko小鼠与载脂蛋白E基因敲除小鼠(ApoE-/-)杂交得到MyD88EC-KO ApoE-/-小鼠和MyD88MC-KO ApoE-/-小鼠.这些小鼠被给予正常饮食或高脂饮食(HFD,从小鼠6周大开始)三个月以建立饮食致肥胖模型及主动脉粥样硬化疾病模型。我们对实验小鼠检测了包括体重、体脂肪量、血脂水平及血糖/胰岛素浓度等代谢指标,同时应用葡萄糖/胰岛素耐量试验来评估其对胰岛素的敏感性。我们向小鼠腹腔注射胰岛素或生理盐水后收集脂肪组织、肌肉组织及肝脏组织,并用western-blot检测胰岛素对IRS-1-PI3K-AKT信号通路的激活。为了检测HFD诱导的全身炎症反应,用ELISA检测血浆内促炎症细胞因子的蛋白水平。通过免疫组化染色观察实验小鼠脂肪组织中巨噬细胞的浸润量,且进一步对基质血管成分细胞染色并予以细胞流式分析巨噬细胞亚型。在主动脉粥样硬化模型中,对实验小鼠主动脉进行油红O染色,用photoshop软件分析图像并计算各基因组平均病变面积。通过免疫荧光染色结合共聚焦显微镜检查病灶内巨噬细胞-粒细胞集落刺激因子(granulocyte-macrophage colony-stimulating factor, GM-CSF)与内皮细胞表面标记CD31共定位。我们建立脂肪细胞和巨噬细胞共培养的方法并且用游离脂肪酸(FFAs)/细菌脂多糖(LPS)刺激巨噬细胞来证实巨噬细胞及脂肪细胞间的相互作用。另一方面,我们提取氧化低密度脂蛋白(oxided low density lipo-ptortein, ox-LDL)刺激后内皮细胞的上清液培养单核/巨噬细胞或直接用ox-LDL刺激GM-CSF促分化的巨噬细胞而阐明内皮细胞及巨噬细胞间的相互作用。上述实验中,RT-PCR用来检测组织/细胞中炎症基因及M1/M2巨噬细胞亚型标志基因的表达水平,而western-blot用来分析各信号通路的激活程度。
实验结果：在高脂饮食小鼠模型中,对骨髓细胞来源MyD88基因的特异性敲除(MyD88MC-KO)能降低全身性炎症反应、胰岛素抵抗及主动脉粥样硬化的程度,同时也能减少脂肪组织中巨噬细胞(ATM)的浸润及ATM从M2抗炎症巨噬细胞亚型向M1促炎症亚型的转变。在此基础上,我们进一步证实了巨噬细胞和脂肪细胞间存在相互作用,而脂肪细胞通过巨噬细胞内MyD88介导的信号通路诱导其M1相关基因的表达。另一方面,内皮细胞特异性敲除MyD88基因小鼠(MyD88EC-KO)体内M1亚型ATM数量,全身炎症反应及主动脉粥样硬化程度与对照组小鼠相比也有一定程度的降低,但不及MyD88MC-KO小鼠表型明显。同时体内及体外实验均表明,内皮细胞来源MyD88依赖生成的GM-CSF因能促使脂肪组织及主动脉组织内巨噬细胞极化为M1亚型而在肥胖致全身性炎症反应及主动脉粥样硬化发展的起始阶段扮演着重要角色。
实验结论：总而言之,这些结果都证明了MyD88介导的信号途径在高脂饮食诱导全身性炎症反应及代谢性炎症疾病发生发展的过程中对脂肪细胞、巨噬细胞及内皮细胞三者间相互联系起着关键作用。
Background:Low grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. A high fat diet (HFD) affects the gut-permeability, triggering the accumulation of systemic inflammatory stimuli, including exogenous and endogenous ligands for interlukin-1receptor (IL-1R)/Toll-like receptors (TLRs). Previous studies suggested a critical role for the EL-1R/TLRs in diet-induced systemic inflammation and obesity-associated inflammatory diseases.
Objectives:In this study, we investigated how TLR-MyD88signaling in different cellular compartments coordinately participates in the initiation of HFD-induced systemic inflammation and metabolic inflammatory diseases.
Methods:We generated endothelial cell-specific MyD88-deficient mice (MyD88EC-KO) and myeloid/macrophage-specific MyD88-deficient mice (MyD88MC-KO) by Cre-LoxP technology. MyD88EC-KO and MyD88MC-KOmice were crossed to ApoE-/-mice to generate MyD88EC-KO ApoE-/-and MyD88MC-KO ApoE-/-mice. We put these mice on chow diet or HFD (starting from6weeks old) for3months to establish diet-induced obesity model and atherosclerosis model. We checked the metabolic profile of these mice including body weight, fat mass, serum cholesterol/triglycerides level and fasting glucose/insulin concentration, performed glucose/insulin tolerance test (GTT/ITT) to evaluate insulin sensitivity. To test the insulin signaling in adipose tissue, muscle and liver, we injected the mice with insulin or saline by I.P., collected tissues and checked insulin stimulated IRS-1-PI3K-AKT signaling by western-blot. To examine HFD-induced systemic inflammation, protein level of pro-inflammatory cytokines in the serum will be analyzed by ELISA. Infiltration of macrophage in adipose tissue (ATM) from the experimental mice was analyzed by immunohisto-chemistry staining, and stromal vascular fraction (SVF) cells were stained followed by flow cytometry analysis. Under ApoE-/-background, enface (oil-red O staining) analysis will be done for the whole aorta tree of the experimental mice. Total mean lesion area will be quantified based on image-analysis by Photoshop software. The co-localization of granulocyte-macrophage colony-stimulating factor (GM-CSF) and endothelial cell surface marker CD31was dected by Immunostaining and examined by confocal microscopy. An adipocyte-macrophage co-culture system and FFA/LPS treatment were used to demonstrate cross-talk between adipocytes and macrophage. We used conditioned medium from endothelial cells treated with ox-LDL to culture monocyte/macrophage and treated GM-CSF primed macrophage with ox-LDL to dress the interplay between endothelial cells and macrophage. Tissue/celluar mRNA was analyzed by RT-PCR to measure the expression of inflammatory genes and markers for M1and M2macrophages. The activation of signal pathway was examined by western-blot.
Results:MyD88deficiency in myeloid cells aborted a switch in ATM phenotype from M2to M1, resulting in substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. Using an adipocyte-macrophage co-culture system, we demonstrated the impact of MyD88-dependent cross-talk between adipocytes and macrophages on Ml macrophages. On the other hand, MyD88deficiency in endothelial cells also showed moderate reduction in diet-induced adipose M1macrophages, systemic inflammation and atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated systemic inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to Ml inflammatory macrophages.
Conclusions:These results suggest that cross-talks among adipocytes, macrophages, and endothelial cells is necessary for establishment of the diet-induced inflammatory state through the production of pro-inflammatory mediators, which in turn cause insulin resistance, leading to inflammatory diseases associated with metabolic syndrome.
实验目的：本研究中,我们旨在探索TLR-MyD88(髓样分化因子88,myeloid differentiation factor88, IL-1R/TLRs主要衔接分子)信号通路是如何在不同细胞类型中协调性地参与HFD诱导的全身性炎症反应及代谢性炎症疾病的起始阶段。
实验方法：我们应用Cre-LoxP基因敲除技术得到内皮细胞特异性MyD88基因敲除小鼠(MyD88EC-KO)及骨髓/巨噬细胞特异性MyD88基因敲除小鼠(MyD88MC-KO).我们又将MyD88EC-KO小鼠与MyD88MC-Ko小鼠与载脂蛋白E基因敲除小鼠(ApoE-/-)杂交得到MyD88EC-KO ApoE-/-小鼠和MyD88MC-KO ApoE-/-小鼠.这些小鼠被给予正常饮食或高脂饮食(HFD,从小鼠6周大开始)三个月以建立饮食致肥胖模型及主动脉粥样硬化疾病模型。我们对实验小鼠检测了包括体重、体脂肪量、血脂水平及血糖/胰岛素浓度等代谢指标,同时应用葡萄糖/胰岛素耐量试验来评估其对胰岛素的敏感性。我们向小鼠腹腔注射胰岛素或生理盐水后收集脂肪组织、肌肉组织及肝脏组织,并用western-blot检测胰岛素对IRS-1-PI3K-AKT信号通路的激活。为了检测HFD诱导的全身炎症反应,用ELISA检测血浆内促炎症细胞因子的蛋白水平。通过免疫组化染色观察实验小鼠脂肪组织中巨噬细胞的浸润量,且进一步对基质血管成分细胞染色并予以细胞流式分析巨噬细胞亚型。在主动脉粥样硬化模型中,对实验小鼠主动脉进行油红O染色,用photoshop软件分析图像并计算各基因组平均病变面积。通过免疫荧光染色结合共聚焦显微镜检查病灶内巨噬细胞-粒细胞集落刺激因子(granulocyte-macrophage colony-stimulating factor, GM-CSF)与内皮细胞表面标记CD31共定位。我们建立脂肪细胞和巨噬细胞共培养的方法并且用游离脂肪酸(FFAs)/细菌脂多糖(LPS)刺激巨噬细胞来证实巨噬细胞及脂肪细胞间的相互作用。另一方面,我们提取氧化低密度脂蛋白(oxided low density lipo-ptortein, ox-LDL)刺激后内皮细胞的上清液培养单核/巨噬细胞或直接用ox-LDL刺激GM-CSF促分化的巨噬细胞而阐明内皮细胞及巨噬细胞间的相互作用。上述实验中,RT-PCR用来检测组织/细胞中炎症基因及M1/M2巨噬细胞亚型标志基因的表达水平,而western-blot用来分析各信号通路的激活程度。
实验结果：在高脂饮食小鼠模型中,对骨髓细胞来源MyD88基因的特异性敲除(MyD88MC-KO)能降低全身性炎症反应、胰岛素抵抗及主动脉粥样硬化的程度,同时也能减少脂肪组织中巨噬细胞(ATM)的浸润及ATM从M2抗炎症巨噬细胞亚型向M1促炎症亚型的转变。在此基础上,我们进一步证实了巨噬细胞和脂肪细胞间存在相互作用,而脂肪细胞通过巨噬细胞内MyD88介导的信号通路诱导其M1相关基因的表达。另一方面,内皮细胞特异性敲除MyD88基因小鼠(MyD88EC-KO)体内M1亚型ATM数量,全身炎症反应及主动脉粥样硬化程度与对照组小鼠相比也有一定程度的降低,但不及MyD88MC-KO小鼠表型明显。同时体内及体外实验均表明,内皮细胞来源MyD88依赖生成的GM-CSF因能促使脂肪组织及主动脉组织内巨噬细胞极化为M1亚型而在肥胖致全身性炎症反应及主动脉粥样硬化发展的起始阶段扮演着重要角色。
实验结论：总而言之,这些结果都证明了MyD88介导的信号途径在高脂饮食诱导全身性炎症反应及代谢性炎症疾病发生发展的过程中对脂肪细胞、巨噬细胞及内皮细胞三者间相互联系起着关键作用。
Background:Low grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. A high fat diet (HFD) affects the gut-permeability, triggering the accumulation of systemic inflammatory stimuli, including exogenous and endogenous ligands for interlukin-1receptor (IL-1R)/Toll-like receptors (TLRs). Previous studies suggested a critical role for the EL-1R/TLRs in diet-induced systemic inflammation and obesity-associated inflammatory diseases.
Objectives:In this study, we investigated how TLR-MyD88signaling in different cellular compartments coordinately participates in the initiation of HFD-induced systemic inflammation and metabolic inflammatory diseases.
Methods:We generated endothelial cell-specific MyD88-deficient mice (MyD88EC-KO) and myeloid/macrophage-specific MyD88-deficient mice (MyD88MC-KO) by Cre-LoxP technology. MyD88EC-KO and MyD88MC-KOmice were crossed to ApoE-/-mice to generate MyD88EC-KO ApoE-/-and MyD88MC-KO ApoE-/-mice. We put these mice on chow diet or HFD (starting from6weeks old) for3months to establish diet-induced obesity model and atherosclerosis model. We checked the metabolic profile of these mice including body weight, fat mass, serum cholesterol/triglycerides level and fasting glucose/insulin concentration, performed glucose/insulin tolerance test (GTT/ITT) to evaluate insulin sensitivity. To test the insulin signaling in adipose tissue, muscle and liver, we injected the mice with insulin or saline by I.P., collected tissues and checked insulin stimulated IRS-1-PI3K-AKT signaling by western-blot. To examine HFD-induced systemic inflammation, protein level of pro-inflammatory cytokines in the serum will be analyzed by ELISA. Infiltration of macrophage in adipose tissue (ATM) from the experimental mice was analyzed by immunohisto-chemistry staining, and stromal vascular fraction (SVF) cells were stained followed by flow cytometry analysis. Under ApoE-/-background, enface (oil-red O staining) analysis will be done for the whole aorta tree of the experimental mice. Total mean lesion area will be quantified based on image-analysis by Photoshop software. The co-localization of granulocyte-macrophage colony-stimulating factor (GM-CSF) and endothelial cell surface marker CD31was dected by Immunostaining and examined by confocal microscopy. An adipocyte-macrophage co-culture system and FFA/LPS treatment were used to demonstrate cross-talk between adipocytes and macrophage. We used conditioned medium from endothelial cells treated with ox-LDL to culture monocyte/macrophage and treated GM-CSF primed macrophage with ox-LDL to dress the interplay between endothelial cells and macrophage. Tissue/celluar mRNA was analyzed by RT-PCR to measure the expression of inflammatory genes and markers for M1and M2macrophages. The activation of signal pathway was examined by western-blot.
Results:MyD88deficiency in myeloid cells aborted a switch in ATM phenotype from M2to M1, resulting in substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. Using an adipocyte-macrophage co-culture system, we demonstrated the impact of MyD88-dependent cross-talk between adipocytes and macrophages on Ml macrophages. On the other hand, MyD88deficiency in endothelial cells also showed moderate reduction in diet-induced adipose M1macrophages, systemic inflammation and atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated systemic inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to Ml inflammatory macrophages.
Conclusions:These results suggest that cross-talks among adipocytes, macrophages, and endothelial cells is necessary for establishment of the diet-induced inflammatory state through the production of pro-inflammatory mediators, which in turn cause insulin resistance, leading to inflammatory diseases associated with metabolic syndrome.
引文
1. Ford, E.S., W.H. Giles, and W.H. Dietz, Prevalence of the metabolic syndrome among US adults:findings from the third National Health and Nutrition Examination Survey. JAMA:the journal of the American Medical Association, 2002.287(3):p.356-9.
2. Cai, D., et al., Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nature medicine,2005.11(2):p.183-90.
3. Arkan, M.C., et al., IKK-beta links inflammation to obesity-induced insulin resistance. Nature medicine,2005.11(2):p.191-8.
4. Hirosumi, J., et al., A central role for JNK in obesity and insulin resistance. Nature, 2002.420(6913):p.333-6.
5. Erridge, C., Diet, commensals and the intestine as sources of pathogen-associated molecular patterns in atherosclerosis, type 2 diabetes and non-alcoholic fatty liver disease. Atherosclerosis,2011.216(1):p.1-6.
6. Creely, S.J., et al., Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. American journal of physiology. Endocrinology and metabolism,2007.292(3):p. E740-7.
7. Dasu, M.R., S. Ramirez, and R.R. Isseroff, Toll-like receptors and diabetes:a therapeutic perspective. Clinical science,2012.122(5):p.203-14.
8. Backhed, F., et al., The gut microbiota as an environmental factor that regulates fat storage. Proceedings of the National Academy of Sciences of the United States of America,2004.101(44):p.15718-23.
9. Cani, P.D., et al., Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes,2007.56(7):p.1761-72.
10. Cani, P.D., et al., Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes,2008. 57(6):p.1470-81.
11. Hotamisligil, G.S., Inflammation and metabolic disorders. Nature,2006.444(7121): p.860-7.
12. Shi, H., et al., TLR4 links innate immunity and fatty acid-induced insulin resistance. The Journal of clinical investigation,2006.116(11):p.3015-25.
13. Himes, R.W. and C.W. Smith, Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB journal:official publication of the Federation of American Societies for Experimental Biology,2010.24(3):p.731-9.
14. Kiechl, S., et al., Toll-like receptor 4 polymorphisms and atherogenesis. The New England journal of medicine,2002.347(3):p.185-92.
15. Bjorkbacka, H., et al., Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature medicine,2004.10(4):p.416-21.
16. Chi, H., et al., Interleukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet in a murine apolipoprotein E heterozygote model:pharmacotherapeutic implications. Circulation,2004.110(12): p.1678-85.
17. Kirii, H., et al., Lack of interleukin-lbeta decreases the severity of atherosclerosis in ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology,2003. 23(4):p.656-60.
18. Michelsen, K.S., et al., Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proceedings of the National Academy of Sciences of the United States of America,2004.101(29):p.10679-84.
19. Fresno, M., R. Alvarez, and N. Cuesta, Toll-like receptors, inflammation, metabolism and obesity. Archives of physiology and biochemistry,2011.117(3):p. 151-64.
20. Konner, A.C. and J.C. Bruning, Toll-like receptors:linking inflammation to metabolism. Trends in endocrinology and metabolism:TEM,2011.22(1):p.16-23.
21. Brown, J., et al., TLR-signaling networks:an integration of adaptor molecules, kinases, and cross-talk. Journal of dental research,2011.90(4):p.417-27.
22. Gay, N.J., M. Gangloff, and L.A. O'Neill, What the Myddosome structure tells us about the initiation of innate immunity. Trends in immunology,2011.32(3):p.104-9.
23. Kenny, E.F. and L.A. O'Neill, Signalling adaptors used by Toll-like receptors:an update. Cytokine,2008.43(3):p.342-9.
24. Lin, S.C., Y.C. Lo, and H. Wu, Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature,2010.465(7300):p.885-90.
25. Takeuchi, O. and S. Akira, MyD88 as a bottle neck in Toll/IL-1 signaling. Current topics in microbiology and immunology,2002.270:p.155-67.
26. Fraczek, J., et al., The kinase activity of IL-1 receptor-associated kinase 4 is required for interleukin-1 receptor/toll-like receptor-induced TAK1-dependent NFkappaB activation. The Journal of biological chemistry,2008.283(46):p.31697-705.
27. Kim, T.W., et al., A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. The Journal of experimental medicine,2007.204(5):p. 1025-36.
28. Yao, J., et al., Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFkappaB activation pathways bifurcate at IL-1 receptor-associated kinase modification. The Journal of biological chemistry,2007.282(9):p.6075-89.
29. Kang, Z., et al., Astrocyte-restricted ablation of interleukin-17-induced Actl-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity,2010. 32(3):p.414-25.
30. Kano, A., et al., Endothelial cells require STAT3 for protection against endotoxin-induced inflammation. The Journal of experimental medicine,2003.198(10):p. 1517-25.
31. Boillee, S., et al., Onset and progression in inherited ALS determined by motor neurons and microglia. Science,2006.312(5778):p.1389-92.
32. Kang, Z., et al., Epithelial cell-specific Actl adaptor mediates interleukin-25-dependent helminth expulsion through expansion of Lin(-)c-Kit(+) innate cell population. Immunity,2012.36(5):p.821-33.
33. Emanuela, F., et al., Inflammation as a Link between Obesity and Metabolic Syndrome. Journal of nutrition and metabolism,2012.2012:p.476380.
34. Monteiro, R. and I. Azevedo, Chronic inflammation in obesity and the metabolic syndrome. Mediators of inflammation,2010.2010.
35. Hotamisligil, GS., N.S. Shargill, and B.M. Spiegelman, Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance. Science, 1993.259(5091):p.87-91.
36. Neels, J.G. and J.M. Olefsky, Inflamed fat:what starts the fire? The Journal of clinical investigation,2006.116(1):p.33-5.
37. Nishimura, S., I. Manabe, and R. Nagai, Adipose tissue inflammation in obesity and metabolic syndrome. Discovery medicine,2009.8(41):p.55-60.
38. Wajchenberg, B.L., et al., Adipose tissue at the crossroads in the development of the metabolic syndrome, inflammation and atherosclerosis. Arquivos brasileiros de endocrinologia e metabologia,2009.53(2):p.145-50.
39. Xu, H., et al., Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of clinical investigation,2003. 112(12):p.1821-30.
40. Weisberg, S.P., et al., Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation,2003.112(12):p.1796-808.
41. Fujisaka, S., et al., Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes,2009.58(11):p.2574-82.
42. Lumeng, C.N., J.L. Bodzin, and A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization. The Journal of clinical investigation, 2007.117(1):p.175-84.
43. Prieur, X., et al., Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes,2011.60(3):p.797-809.
44. Fleetwood, A.J., et al., GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. Journal of leukocyte biology,2009.86(2):p.411-21.
45. Seimon, T.A., et al., Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell metabolism,2010.12(5):p.467-82.
46. Su, X., et al., Oxidized low density lipoprotein induces bone morphogenetic protein-2 in coronary artery endothelial cells via Toll-like receptors 2 and 4. The Journal of biological chemistry,2011.286(14):p.12213-20.
47. Aird, W.C., Phenotypic heterogeneity of the endothelium:Ⅰ. Structure, function, and mechanisms. Circulation research,2007.100(2):p.158-73.
48. Brocheriou, I., et al., Antagonistic regulation of macrophage phenotype by M-CSF and GM-CSF:implication in atherosclerosis. Atherosclerosis,2011.214(2):p.316-24.
49. Chinetti-Gbaguidi, G. and B. Staels, Macrophage polarization in metabolic disorders: functions and regulation. Current opinion in lipidology,2011.22(5):p.365-72.
50. Harari, O.A., et al., Absence of TRAM restricts Toll-like receptor 4 signaling in vascular endothelial cells to the MyD88 pathway. Circulation research,2006.98(9): p.1134-40.
51. Staels, B., Cardiovascular biology:a cholesterol tether. Nature,2002.417(6890):p. 699-701.
52. Haghighat, A., et al., Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor exacerbate atherosclerosis in apolipoprotein E-deficient mice. Circulation,2007.115(15):p.2049-54.
53. Zhu, S.N., et al., GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions. The Journal of experimental medicine,2009.206(10):p. 2141-9.
54. Semenkovich, C.F., Insulin resistance and atherosclerosis. The Journal of clinical investigation,2006.116(7):p.1813-22.
55. Miyazaki, T., J. Kurokawa, and S. Arai, AIMing at metabolic syndrome.-Towards the development of novel therapies for metabolic diseases via apoptosis inhibitor of macrophage (AIM). Circulation journal:official journal of the Japanese Circulation Society,2011.75(11):p.2522-31.
56. Suganami, T., J. Nishida, and Y. Ogawa, A paracrine loop between adipocytes and macrophages aggravates inflammatory changes:role of free fatty acids and tumor necrosis factor alpha. Arteriosclerosis, thrombosis, and vascular biology,2005. 25(10):p.2062-8.
57. Wen, H., et al., Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature immunology,2011.12(5):p.408-15.
1. Adamczak, M. and A. Wiecek, The adipose tissue as an endocrine organ. Seminars in nephrology,2013.33(1):p.2-13.
2. Hotamisligil, G.S., Inflammation and metabolic disorders. Nature,2006.444(7121): p.860-7.
3. Zhang, Y., et al., Positional cloning of the mouse obese gene and its human homologue. Nature,1994.372(6505):p.425-32.
4. Friedman, J.M., Obesity:Causes and control of excess body fat. Nature,2009. 459(7245):p.340-2.
5. Gao, Q., et al., Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proceedings of the National Academy of Sciences of the United States of America,2004.101(13):p. 4661-6.
6. Belgardt, B.F., et al., PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell metabolism,2008.7(4):p.291-301.
7. Hill, J.W., et al., Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. The Journal of clinical investigation,2008. 118(5):p.1796-805.
8. Bates, S.H., et al., STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature,2003.421(6925):p.856-9.
9. Ernst, M.B., et al., Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. The Journal of neuroscience:the official journal of the Society for Neuroscience,2009.29(37):p. 11582-93.
10. Sanchez-Lasheras, C., A.C. Konner, and J.C. Bruning, Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators. Frontiers in neuroendocrinology,2010.31(1):p.4-15.
11. Gropp, E., et al., Agouti-related peptide-expressing neurons are mandatory for feeding. Nature neuroscience,2005.8(10):p.1289-91.
12. Luquet, S., et al., NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science,2005.310(5748):p.683-5.
13. Plum, L., et al., Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. The Journal of clinical investigation, 2006.116(7):p.1886-901.
14. Plum, L., et al., Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation. Cell metabolism,2007.6(6):p.431-45.
15. El-Haschimi, K., et al., Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. The Journal of clinical investigation,2000.105(12): p.1827-32.
16. Bruning, J.C., et al., Role of brain insulin receptor in control of body weight and reproduction. Science,2000.289(5487):p.2122-5.
17. Seino, S. and T. Miki, Physiological and pathophysiological roles of ATP-sensitive K+ channels. Progress in biophysics and molecular biology,2003.81(2):p.133-76.
18. Ferreira, A.V., et al., High-carbohydrate diet selectively induces tumor necrosis factor-alpha production in mice liver. Inflammation,2011.34(2):p.139-45.
19. Plum, L., M. Schubert, and J.C. Bruning, The role of insulin receptor signaling in the brain. Trends in endocrinology and metabolism:TEM,2005.16(2):p.59-65.
20. Plum, L., B.F. Belgardt, and J.C. Bruning, Central insulin action in energy and glucose homeostasis. The Journal of clinical investigation,2006.116(7):p.1761-6.
21. Wellen, K.E. and G.S. Hotamisligil, Inflammation, stress, and diabetes. The Journal of clinical investigation,2005.115(5):p.1111-9.
22. Galic, S., J.S. Oakhill, and G.R. Steinberg, Adipose tissue as an endocrine organ. Molecular and cellular endocrinology,2010.316(2):p.129-39.
23. Uysal, K.T., et al., Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature,1997.389(6651):p.610-4.
24. Weisberg, S.P., et al., Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation,2003.112(12):p.1796-808.
25. Xu, H., et al., Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of clinical investigation,2003.112(12): p.1821-30.
26. Charriere, G., et al., Preadipocyte conversion to macrophage. Evidence of plasticity. The Journal of biological chemistry,2003.278(11):p.9850-5.
27. Hotamisligil, G.S. and E. Erbay, Nutrient sensing and inflammation in metabolic diseases. Nature reviews. Immunology,2008.8(12):p.923-34.
28. Hotamisligil, G.S., N.S. Shargill, and B.M. Spiegelman, Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance. Science,1993. 259(5091):p.87-91.
29. Fernandez-Veledo, S., et al., Molecular mechanisms involved in obesity-associated insulin resistance:therapeutical approach. Archives of physiology and biochemistry, 2009.115(4):p.227-39.
30. Starr, M.E., B.M. Evers, and H. Saito, Age-associated increase in cytokine production during systemic inflammation:adipose tissue as a major source of IL-6. The journals of gerontology. Series A, Biological sciences and medical sciences, 2009.64(7):p.723-30.
31. Fain, J.N., Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells:a review. Mediators of inflammation, 2010.2010:p.513948.
32. Lumeng, C.N., J.L. Bodzin, and A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization. The Journal of clinical investigation,2007. 117(1):p.175-84.
33. Lin, S.C., Y.C. Lo, and H. Wu, Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature,2010.465(7300):p.885-90.
34. Suganami, T. and Y. Ogawa, Adipose tissue macrophages:their role in adipose tissue remodeling. Journal of leukocyte biology,2010.88(1):p.33-9.
35. Schaeffler, A., et al., Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology,2009.126(2):p.233-45.
36. Netea, M.G., et al., Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nature medicine,2006.12(6):p.650-6.
37. Wunderlich, F.T., et al., Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell metabolism,2010. 12(3):p.237-49.
38. Hirosumi, J., et al., A central role for JNK in obesity and insulin resistance. Nature, 2002.420(6913):p.333-6.
39. Arkan, M.C., et al., IKK-beta links inflammation to obesity-induced insulin resistance. Nature medicine,2005.11(2):p.191-8.
40. Schmitz-Peiffer, C. and T.J. Biden, Protein kinase C function in muscle, liver, and beta-cells and its therapeutic implications for type 2 diabetes. Diabetes,2008.57(7): p.1774-83.
41. Ozcan, U., et al., Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science,2004.306(5695):p.457-61.
42. Belgardt, B.F., et al., Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism. Proceedings of the National Academy of Sciences of the United States of America,2010.107(13):p.6028-33.
43. Shoelson, S.E., J. Lee, and M. Yuan, Inflammation and the IKK beta/Ⅰ kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. International journal of obesity and related metabolic disorders:journal of the International Association for the Study of Obesity,2003.27 Suppl 3:p. S49-52.
44. Cai, D., et al., Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nature medicine,2005.11(2):p.183-90.
45. Wunderlich, F.T., et al., Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America,2008.105(4):p.1297-302.
46. Shi, H., et al., TLR4 links innate immunity and fatty acid-induced insulin resistance. The Journal of clinical investigation,2006.116(11):p.3015-25.
47. Poggi, M., et al., C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia,2007.50(6):p.1267-76.
48. Kim, F., et al., Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circulation research,2007.100(11):p.1589-96.
49. Staiger, H., et al., Palmitate-induced interleukin-6 expression in human coronary artery endothelial cells. Diabetes,2004.53(12):p.3209-16.
50. Senn, J.J., Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes. The Journal of biological chemistry,2006.281(37):p. 26865-75.
51. Kawai, T., et al., Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity, 1999.11(1):p.115-22.
52. Pasare, C. and R. Medzhitov, Toll-like receptors:linking innate and adaptive immunity. Microbes and infection/Institut Pasteur,2004.6(15):p.1382-7.
53. Kirii, H., et al., Lack of interleukin-lbeta decreases the severity of atherosclerosis in ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology,2003.23(4): p.656-60.
54. Hommelberg, P.P., et al., Fatty acid-induced NF-kappaB activation and insulin resistance in skeletal muscle are chain length dependent. American journal of physiology. Endocrinology and metabolism,2009.296(1):p. E114-20.
55. Davis, J.E., et al., Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity,2008.16(6):p.1248-55.
56. Saberi, M., et al., Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell metabolism,2009.10(5):p.419-29.
57. Reyna, S.M., et al., Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes,2008.57(10):p.2595-602.
58. Summers, S.A. and D.H. Nelson, A role for sphingolipids in producing the common features of type 2 diabetes, metabolic syndrome X, and Cushing's syndrome. Diabetes,2005.54(3):p.591-602.
59. Holland, W.L., et al., Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell metabolism,2007.5(3):p. 167-79.
60. Turnbaugh, P.J., et al., An obesity-associated gut microbiome with increased capacity for energy harvest. Nature,2006.444(7122):p.1027-31.
61. Cani, P.D., et al., Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes,2007.56(7):p.1761-72.
62. Woods, S.C., et al., Consumption of a high-fat diet alters the homeostatic regulation of energy balance. Physiology & behavior,2004.83(4):p.573-8.
63. Enriori, P.J., et al., Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell metabolism,2007.5(3):p.181-94.
64. Kleinridders, A., et al., MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell metabolism,2009. 10(4):p.249-59.
65. Zhang, X., et al., Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell,2008.135(1):p.61-73.
66. Milanski, M., et al., Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. The Journal of neuroscience:the official journal of the Society for Neuroscience 2009.29(2):p.359-70.
67. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE, Gewirtz AT. (2010).Metabolic syndrome and altered gut microbiota in mice lackingToll-like receptor 5. Science 328:228-31.
68. Elgazar-Carmon V, Rudich A, Hadad N, Levy R. (2008). Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res. 49:1894-903.
69. Lehrke M, Lazar MA. (2004). Inflamed about obesity. Nat Med.10:126-7.
70. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, et al. (2009). CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med.15:914-20.
71. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, et al. (2009). Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med.15:930-39.
72. Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, Joosten LA, Akira S, Netea MG, Adema GJ. (2006).Tolllike receptor 2 controls expansion and function of regulatory T cells. J Clin Invest.116:485-94.
2. Cai, D., et al., Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nature medicine,2005.11(2):p.183-90.
3. Arkan, M.C., et al., IKK-beta links inflammation to obesity-induced insulin resistance. Nature medicine,2005.11(2):p.191-8.
4. Hirosumi, J., et al., A central role for JNK in obesity and insulin resistance. Nature, 2002.420(6913):p.333-6.
5. Erridge, C., Diet, commensals and the intestine as sources of pathogen-associated molecular patterns in atherosclerosis, type 2 diabetes and non-alcoholic fatty liver disease. Atherosclerosis,2011.216(1):p.1-6.
6. Creely, S.J., et al., Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. American journal of physiology. Endocrinology and metabolism,2007.292(3):p. E740-7.
7. Dasu, M.R., S. Ramirez, and R.R. Isseroff, Toll-like receptors and diabetes:a therapeutic perspective. Clinical science,2012.122(5):p.203-14.
8. Backhed, F., et al., The gut microbiota as an environmental factor that regulates fat storage. Proceedings of the National Academy of Sciences of the United States of America,2004.101(44):p.15718-23.
9. Cani, P.D., et al., Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes,2007.56(7):p.1761-72.
10. Cani, P.D., et al., Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes,2008. 57(6):p.1470-81.
11. Hotamisligil, G.S., Inflammation and metabolic disorders. Nature,2006.444(7121): p.860-7.
12. Shi, H., et al., TLR4 links innate immunity and fatty acid-induced insulin resistance. The Journal of clinical investigation,2006.116(11):p.3015-25.
13. Himes, R.W. and C.W. Smith, Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB journal:official publication of the Federation of American Societies for Experimental Biology,2010.24(3):p.731-9.
14. Kiechl, S., et al., Toll-like receptor 4 polymorphisms and atherogenesis. The New England journal of medicine,2002.347(3):p.185-92.
15. Bjorkbacka, H., et al., Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature medicine,2004.10(4):p.416-21.
16. Chi, H., et al., Interleukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet in a murine apolipoprotein E heterozygote model:pharmacotherapeutic implications. Circulation,2004.110(12): p.1678-85.
17. Kirii, H., et al., Lack of interleukin-lbeta decreases the severity of atherosclerosis in ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology,2003. 23(4):p.656-60.
18. Michelsen, K.S., et al., Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proceedings of the National Academy of Sciences of the United States of America,2004.101(29):p.10679-84.
19. Fresno, M., R. Alvarez, and N. Cuesta, Toll-like receptors, inflammation, metabolism and obesity. Archives of physiology and biochemistry,2011.117(3):p. 151-64.
20. Konner, A.C. and J.C. Bruning, Toll-like receptors:linking inflammation to metabolism. Trends in endocrinology and metabolism:TEM,2011.22(1):p.16-23.
21. Brown, J., et al., TLR-signaling networks:an integration of adaptor molecules, kinases, and cross-talk. Journal of dental research,2011.90(4):p.417-27.
22. Gay, N.J., M. Gangloff, and L.A. O'Neill, What the Myddosome structure tells us about the initiation of innate immunity. Trends in immunology,2011.32(3):p.104-9.
23. Kenny, E.F. and L.A. O'Neill, Signalling adaptors used by Toll-like receptors:an update. Cytokine,2008.43(3):p.342-9.
24. Lin, S.C., Y.C. Lo, and H. Wu, Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature,2010.465(7300):p.885-90.
25. Takeuchi, O. and S. Akira, MyD88 as a bottle neck in Toll/IL-1 signaling. Current topics in microbiology and immunology,2002.270:p.155-67.
26. Fraczek, J., et al., The kinase activity of IL-1 receptor-associated kinase 4 is required for interleukin-1 receptor/toll-like receptor-induced TAK1-dependent NFkappaB activation. The Journal of biological chemistry,2008.283(46):p.31697-705.
27. Kim, T.W., et al., A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. The Journal of experimental medicine,2007.204(5):p. 1025-36.
28. Yao, J., et al., Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFkappaB activation pathways bifurcate at IL-1 receptor-associated kinase modification. The Journal of biological chemistry,2007.282(9):p.6075-89.
29. Kang, Z., et al., Astrocyte-restricted ablation of interleukin-17-induced Actl-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity,2010. 32(3):p.414-25.
30. Kano, A., et al., Endothelial cells require STAT3 for protection against endotoxin-induced inflammation. The Journal of experimental medicine,2003.198(10):p. 1517-25.
31. Boillee, S., et al., Onset and progression in inherited ALS determined by motor neurons and microglia. Science,2006.312(5778):p.1389-92.
32. Kang, Z., et al., Epithelial cell-specific Actl adaptor mediates interleukin-25-dependent helminth expulsion through expansion of Lin(-)c-Kit(+) innate cell population. Immunity,2012.36(5):p.821-33.
33. Emanuela, F., et al., Inflammation as a Link between Obesity and Metabolic Syndrome. Journal of nutrition and metabolism,2012.2012:p.476380.
34. Monteiro, R. and I. Azevedo, Chronic inflammation in obesity and the metabolic syndrome. Mediators of inflammation,2010.2010.
35. Hotamisligil, GS., N.S. Shargill, and B.M. Spiegelman, Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance. Science, 1993.259(5091):p.87-91.
36. Neels, J.G. and J.M. Olefsky, Inflamed fat:what starts the fire? The Journal of clinical investigation,2006.116(1):p.33-5.
37. Nishimura, S., I. Manabe, and R. Nagai, Adipose tissue inflammation in obesity and metabolic syndrome. Discovery medicine,2009.8(41):p.55-60.
38. Wajchenberg, B.L., et al., Adipose tissue at the crossroads in the development of the metabolic syndrome, inflammation and atherosclerosis. Arquivos brasileiros de endocrinologia e metabologia,2009.53(2):p.145-50.
39. Xu, H., et al., Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of clinical investigation,2003. 112(12):p.1821-30.
40. Weisberg, S.P., et al., Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation,2003.112(12):p.1796-808.
41. Fujisaka, S., et al., Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes,2009.58(11):p.2574-82.
42. Lumeng, C.N., J.L. Bodzin, and A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization. The Journal of clinical investigation, 2007.117(1):p.175-84.
43. Prieur, X., et al., Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes,2011.60(3):p.797-809.
44. Fleetwood, A.J., et al., GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. Journal of leukocyte biology,2009.86(2):p.411-21.
45. Seimon, T.A., et al., Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell metabolism,2010.12(5):p.467-82.
46. Su, X., et al., Oxidized low density lipoprotein induces bone morphogenetic protein-2 in coronary artery endothelial cells via Toll-like receptors 2 and 4. The Journal of biological chemistry,2011.286(14):p.12213-20.
47. Aird, W.C., Phenotypic heterogeneity of the endothelium:Ⅰ. Structure, function, and mechanisms. Circulation research,2007.100(2):p.158-73.
48. Brocheriou, I., et al., Antagonistic regulation of macrophage phenotype by M-CSF and GM-CSF:implication in atherosclerosis. Atherosclerosis,2011.214(2):p.316-24.
49. Chinetti-Gbaguidi, G. and B. Staels, Macrophage polarization in metabolic disorders: functions and regulation. Current opinion in lipidology,2011.22(5):p.365-72.
50. Harari, O.A., et al., Absence of TRAM restricts Toll-like receptor 4 signaling in vascular endothelial cells to the MyD88 pathway. Circulation research,2006.98(9): p.1134-40.
51. Staels, B., Cardiovascular biology:a cholesterol tether. Nature,2002.417(6890):p. 699-701.
52. Haghighat, A., et al., Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor exacerbate atherosclerosis in apolipoprotein E-deficient mice. Circulation,2007.115(15):p.2049-54.
53. Zhu, S.N., et al., GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions. The Journal of experimental medicine,2009.206(10):p. 2141-9.
54. Semenkovich, C.F., Insulin resistance and atherosclerosis. The Journal of clinical investigation,2006.116(7):p.1813-22.
55. Miyazaki, T., J. Kurokawa, and S. Arai, AIMing at metabolic syndrome.-Towards the development of novel therapies for metabolic diseases via apoptosis inhibitor of macrophage (AIM). Circulation journal:official journal of the Japanese Circulation Society,2011.75(11):p.2522-31.
56. Suganami, T., J. Nishida, and Y. Ogawa, A paracrine loop between adipocytes and macrophages aggravates inflammatory changes:role of free fatty acids and tumor necrosis factor alpha. Arteriosclerosis, thrombosis, and vascular biology,2005. 25(10):p.2062-8.
57. Wen, H., et al., Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature immunology,2011.12(5):p.408-15.
1. Adamczak, M. and A. Wiecek, The adipose tissue as an endocrine organ. Seminars in nephrology,2013.33(1):p.2-13.
2. Hotamisligil, G.S., Inflammation and metabolic disorders. Nature,2006.444(7121): p.860-7.
3. Zhang, Y., et al., Positional cloning of the mouse obese gene and its human homologue. Nature,1994.372(6505):p.425-32.
4. Friedman, J.M., Obesity:Causes and control of excess body fat. Nature,2009. 459(7245):p.340-2.
5. Gao, Q., et al., Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proceedings of the National Academy of Sciences of the United States of America,2004.101(13):p. 4661-6.
6. Belgardt, B.F., et al., PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell metabolism,2008.7(4):p.291-301.
7. Hill, J.W., et al., Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. The Journal of clinical investigation,2008. 118(5):p.1796-805.
8. Bates, S.H., et al., STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature,2003.421(6925):p.856-9.
9. Ernst, M.B., et al., Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. The Journal of neuroscience:the official journal of the Society for Neuroscience,2009.29(37):p. 11582-93.
10. Sanchez-Lasheras, C., A.C. Konner, and J.C. Bruning, Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators. Frontiers in neuroendocrinology,2010.31(1):p.4-15.
11. Gropp, E., et al., Agouti-related peptide-expressing neurons are mandatory for feeding. Nature neuroscience,2005.8(10):p.1289-91.
12. Luquet, S., et al., NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science,2005.310(5748):p.683-5.
13. Plum, L., et al., Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. The Journal of clinical investigation, 2006.116(7):p.1886-901.
14. Plum, L., et al., Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation. Cell metabolism,2007.6(6):p.431-45.
15. El-Haschimi, K., et al., Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. The Journal of clinical investigation,2000.105(12): p.1827-32.
16. Bruning, J.C., et al., Role of brain insulin receptor in control of body weight and reproduction. Science,2000.289(5487):p.2122-5.
17. Seino, S. and T. Miki, Physiological and pathophysiological roles of ATP-sensitive K+ channels. Progress in biophysics and molecular biology,2003.81(2):p.133-76.
18. Ferreira, A.V., et al., High-carbohydrate diet selectively induces tumor necrosis factor-alpha production in mice liver. Inflammation,2011.34(2):p.139-45.
19. Plum, L., M. Schubert, and J.C. Bruning, The role of insulin receptor signaling in the brain. Trends in endocrinology and metabolism:TEM,2005.16(2):p.59-65.
20. Plum, L., B.F. Belgardt, and J.C. Bruning, Central insulin action in energy and glucose homeostasis. The Journal of clinical investigation,2006.116(7):p.1761-6.
21. Wellen, K.E. and G.S. Hotamisligil, Inflammation, stress, and diabetes. The Journal of clinical investigation,2005.115(5):p.1111-9.
22. Galic, S., J.S. Oakhill, and G.R. Steinberg, Adipose tissue as an endocrine organ. Molecular and cellular endocrinology,2010.316(2):p.129-39.
23. Uysal, K.T., et al., Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature,1997.389(6651):p.610-4.
24. Weisberg, S.P., et al., Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation,2003.112(12):p.1796-808.
25. Xu, H., et al., Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of clinical investigation,2003.112(12): p.1821-30.
26. Charriere, G., et al., Preadipocyte conversion to macrophage. Evidence of plasticity. The Journal of biological chemistry,2003.278(11):p.9850-5.
27. Hotamisligil, G.S. and E. Erbay, Nutrient sensing and inflammation in metabolic diseases. Nature reviews. Immunology,2008.8(12):p.923-34.
28. Hotamisligil, G.S., N.S. Shargill, and B.M. Spiegelman, Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance. Science,1993. 259(5091):p.87-91.
29. Fernandez-Veledo, S., et al., Molecular mechanisms involved in obesity-associated insulin resistance:therapeutical approach. Archives of physiology and biochemistry, 2009.115(4):p.227-39.
30. Starr, M.E., B.M. Evers, and H. Saito, Age-associated increase in cytokine production during systemic inflammation:adipose tissue as a major source of IL-6. The journals of gerontology. Series A, Biological sciences and medical sciences, 2009.64(7):p.723-30.
31. Fain, J.N., Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells:a review. Mediators of inflammation, 2010.2010:p.513948.
32. Lumeng, C.N., J.L. Bodzin, and A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization. The Journal of clinical investigation,2007. 117(1):p.175-84.
33. Lin, S.C., Y.C. Lo, and H. Wu, Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature,2010.465(7300):p.885-90.
34. Suganami, T. and Y. Ogawa, Adipose tissue macrophages:their role in adipose tissue remodeling. Journal of leukocyte biology,2010.88(1):p.33-9.
35. Schaeffler, A., et al., Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology,2009.126(2):p.233-45.
36. Netea, M.G., et al., Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nature medicine,2006.12(6):p.650-6.
37. Wunderlich, F.T., et al., Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell metabolism,2010. 12(3):p.237-49.
38. Hirosumi, J., et al., A central role for JNK in obesity and insulin resistance. Nature, 2002.420(6913):p.333-6.
39. Arkan, M.C., et al., IKK-beta links inflammation to obesity-induced insulin resistance. Nature medicine,2005.11(2):p.191-8.
40. Schmitz-Peiffer, C. and T.J. Biden, Protein kinase C function in muscle, liver, and beta-cells and its therapeutic implications for type 2 diabetes. Diabetes,2008.57(7): p.1774-83.
41. Ozcan, U., et al., Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science,2004.306(5695):p.457-61.
42. Belgardt, B.F., et al., Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism. Proceedings of the National Academy of Sciences of the United States of America,2010.107(13):p.6028-33.
43. Shoelson, S.E., J. Lee, and M. Yuan, Inflammation and the IKK beta/Ⅰ kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. International journal of obesity and related metabolic disorders:journal of the International Association for the Study of Obesity,2003.27 Suppl 3:p. S49-52.
44. Cai, D., et al., Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nature medicine,2005.11(2):p.183-90.
45. Wunderlich, F.T., et al., Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America,2008.105(4):p.1297-302.
46. Shi, H., et al., TLR4 links innate immunity and fatty acid-induced insulin resistance. The Journal of clinical investigation,2006.116(11):p.3015-25.
47. Poggi, M., et al., C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia,2007.50(6):p.1267-76.
48. Kim, F., et al., Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circulation research,2007.100(11):p.1589-96.
49. Staiger, H., et al., Palmitate-induced interleukin-6 expression in human coronary artery endothelial cells. Diabetes,2004.53(12):p.3209-16.
50. Senn, J.J., Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes. The Journal of biological chemistry,2006.281(37):p. 26865-75.
51. Kawai, T., et al., Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity, 1999.11(1):p.115-22.
52. Pasare, C. and R. Medzhitov, Toll-like receptors:linking innate and adaptive immunity. Microbes and infection/Institut Pasteur,2004.6(15):p.1382-7.
53. Kirii, H., et al., Lack of interleukin-lbeta decreases the severity of atherosclerosis in ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology,2003.23(4): p.656-60.
54. Hommelberg, P.P., et al., Fatty acid-induced NF-kappaB activation and insulin resistance in skeletal muscle are chain length dependent. American journal of physiology. Endocrinology and metabolism,2009.296(1):p. E114-20.
55. Davis, J.E., et al., Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity,2008.16(6):p.1248-55.
56. Saberi, M., et al., Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell metabolism,2009.10(5):p.419-29.
57. Reyna, S.M., et al., Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes,2008.57(10):p.2595-602.
58. Summers, S.A. and D.H. Nelson, A role for sphingolipids in producing the common features of type 2 diabetes, metabolic syndrome X, and Cushing's syndrome. Diabetes,2005.54(3):p.591-602.
59. Holland, W.L., et al., Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell metabolism,2007.5(3):p. 167-79.
60. Turnbaugh, P.J., et al., An obesity-associated gut microbiome with increased capacity for energy harvest. Nature,2006.444(7122):p.1027-31.
61. Cani, P.D., et al., Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes,2007.56(7):p.1761-72.
62. Woods, S.C., et al., Consumption of a high-fat diet alters the homeostatic regulation of energy balance. Physiology & behavior,2004.83(4):p.573-8.
63. Enriori, P.J., et al., Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell metabolism,2007.5(3):p.181-94.
64. Kleinridders, A., et al., MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell metabolism,2009. 10(4):p.249-59.
65. Zhang, X., et al., Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell,2008.135(1):p.61-73.
66. Milanski, M., et al., Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. The Journal of neuroscience:the official journal of the Society for Neuroscience 2009.29(2):p.359-70.
67. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE, Gewirtz AT. (2010).Metabolic syndrome and altered gut microbiota in mice lackingToll-like receptor 5. Science 328:228-31.
68. Elgazar-Carmon V, Rudich A, Hadad N, Levy R. (2008). Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res. 49:1894-903.
69. Lehrke M, Lazar MA. (2004). Inflamed about obesity. Nat Med.10:126-7.
70. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, et al. (2009). CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med.15:914-20.
71. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, et al. (2009). Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med.15:930-39.
72. Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, Joosten LA, Akira S, Netea MG, Adema GJ. (2006).Tolllike receptor 2 controls expansion and function of regulatory T cells. J Clin Invest.116:485-94.