脂肪细胞因子TNF-α与resistin的表达及其对猪脂肪代谢的调控作用
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摘要
脂肪组织曾一直被认为是一个被动的无活性的组织。然而，近二十多年的发现证明脂肪组织不单是一个能量储存器，更是一个重要的内分泌器官。它能分泌许多因子，包括瘦素(leptin)，肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)，Adiponectin和Resistin等，这些因子统称为脂肪细胞因子(adipokine)，它们在脂代谢和能量平衡中发挥着重要的作用。
肿瘤坏死因子-α是一个多功能细胞因子。在细胞中先合成一个26kDa的跨膜型TNF前体(membrane-bound precursor，mTNF-α)，mTNF-α再经过TNF-转换酶(TNF-α-converting enzyme，TACE)的切割作用在细胞表面裂解产生17kDa的游离型TNF(soluble TNF-α，sTNF-α)。近年来，肿瘤坏死因子在脂肪代谢和胰岛素活性方面的调节作用已有了不少的报道，但大部分报道都是针对在啮齿动物和人类的研究，很少有人用家养动物作为研究对象，而且这些报道未能将mTNF-α和sTNF-α的活性区分开来。
Resistin是新近发现的一个富含半胱氨酸家族成员，Resistin对脂肪转化具有抑制作用，故被推断是脂肪生成的一个反馈调节子或者是限制脂肪形成的一个重要信号分子。关于resistin与脂肪代谢的关系目前才刚刚起步，尤其它与脂肪分解途径的关系几乎还没有过报道。
本研究以遗传性脂肪型和瘦肉型猪作为研究对象，通过半定量RT-PCR和Western Blot等方法，首先，对不同品种，不同生长期猪脂肪组织中的TNF-α表达水平进行了研究；其二，分析了不同生长期猪脂肪组织中TNF-α受体(TNF-α receptor，TNFR)和TNF-转换酶及不同组织中TNF-转换酶表达水平的消长情况，以了解TNF-α受体和TNF-转换酶在脂肪组织中的表达模式是否与TNF-α保持一致；其三，比较了限食条件下，mTNF-α，sTNF-α和TACE在脂肪型猪脂肪组织中的表达差异，以研究它们三者之间及它们与脂肪沉积之间的关系；其四，为了了解Resistin在猪体内表达的特征，本研究从mRNA和蛋白质水平上研究了不同生长
期遗传脂肪型和瘦肉型猪脂肪组织中Reaistin的表达水平差异;其五,为了研究
Resistin与脂肪沉积的关系,本研究分析了不同的限食时间猪脂肪组织中Resistin
水平的变化;其六,为了确定TNF一a和Resistin是否可能通过cAMP路径参与脂
肪分解的调节,本研究对食物限制少R)或饱食(Contr01)猪血液和脂肪中一些脂肪
分解相关的参数进行了检测;最后,本研究分析了Resistin在猪脂肪组织中细胞表
达分布。
根据研究的实验结果,得出以下几个结论:l)m介吓一a,sTNF一a,TACE和
Resistin在猪脂肪组织中都有表达,而且它们的表达水平与脂肪沉积成正比;2)脂
肪沉积的减少导致了TNF一a和Resistin水平及一些脂肪分解相关参数的减少,表
明这两个脂肪细胞因子与脂肪分解途径存在着可能的关系;3) TACE可能调控着
mTNF一a和s翎F一a之间的比率;4) Resistin不仅在脂肪细胞中表达,而且还在其它
细胞型中表达,暗示了Resistin可能还具有除调节脂肪代谢以外的其它生物学活
性。
关键词脂肪组织TNF一a resistin表达与调控脂肪分解细胞分布
Adipose tissue has long been considered to be a passive, inactive tissue. However, it is now widely accepted that adipose tissue secretes a number of peptide hormones including leptin, tumor necrosis factor-alpha (TNF-α), adiponectin and resistin etc, which affect insulin action and energy homeostasis. These newly discovered functions have changed our view that adipose tissue is no longer considered only as an energy storage tissue but as a major endocrine organ.TNF-α is a multifunctional cytokine. TNF-α exists as a 26kDa membrane-bound precursor(mTNF-α), which can be processed at the cell surface by a TNF-α-converting enzyme (TACE) to genernate a 17-kDa soluble form (sTNF-α). Much effort has been focused recently on understanding the role of tumor necrosis factor-a (TNF-α) in regulating fat metabolism and insulin action in rodents and humans, however, there are few reports in domestic animals. Furthermore, to my knowledge, previous few studies distinguished the functions of mTNF-α from that of sTNF-α.Resistin is a member of the newjy discovered cysteine-rich secretory protein family. Some studies demonstrated that resistin had an inhibitory effect on adipose conversion. Therefore, resistin is speculated to be a feedback regulator of adipogenesis and a signal to restrict adipose tissue formation. It is just a start about the study of resistin actions, in particular about the relationship between resistin and lipolysis pathway.In the present study, we employ genetically obese and lean pigs as subjects. Through semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting analysis, we performed the following studies: firstly, we determined the levels of TNF-a expression in adipose tissue of different growth-stage genetically lean and obese pigs; secondly, to analyze whether the expression pattern
between TNF-α receptor (TNFR) or TACE and TNF-α is consistent or not, we examined the levels of TNF-α receptor (TNFR) and TACE in adipose tissue or other tissues from different growth-stage pigs; thirdly, to study the relationship among mTNF-α, sTNF-α and TACE as well as the relationship between them and fat deposition, we analyzed the changes of the levels of mTNF-α, sTNF-α and TACE in adipose tissue from feeding-restricted group(FR) and control group(C); fourthly, to know the characteristic of resistin expression in pigs, we determined the levels of resistin mRNA and protein in adipose tissue of different growth-stage genetically lean and obese pigs; fifthly, to understand the relationship between resistin and fat deposition, we examined the adipose amount of resistin at different time points of feeding restriction for pigs;sixthly, to know whether TNF-α and resistin regulate lipolysis via cAMP pathway, we analyzed the variations of TNF-α and resistin as well as some parameters associated with lipolysis pathway after body-weight reduction in feeding-restricted obese pigs; finally, we localized resistin expression in the cell types from pig adipose tissue.On basis of the results of our experiments, we draw a few following conclusions: 1) TNF-α, TNFR, TACE and resistin could be expressed in adipose tissue of pigs, furthermore, the levels of their expression were positively associated with fat deposition; 2) The decrease of fat deposition result in the reduction of TNF-α and resistin as well as some parameters associated with lipolysis pathway, suggesting the possible association between the two adipocytekines and lipolysis pathway; 3) TACE might play the important regulation in the ratio of mTNF-α to sTNF-α; 4) resistin was expessed not only in adipocytes but also in non-fat cells, indicating other biology actions of resistin.
肿瘤坏死因子-α是一个多功能细胞因子。在细胞中先合成一个26kDa的跨膜型TNF前体(membrane-bound precursor，mTNF-α)，mTNF-α再经过TNF-转换酶(TNF-α-converting enzyme，TACE)的切割作用在细胞表面裂解产生17kDa的游离型TNF(soluble TNF-α，sTNF-α)。近年来，肿瘤坏死因子在脂肪代谢和胰岛素活性方面的调节作用已有了不少的报道，但大部分报道都是针对在啮齿动物和人类的研究，很少有人用家养动物作为研究对象，而且这些报道未能将mTNF-α和sTNF-α的活性区分开来。
Resistin是新近发现的一个富含半胱氨酸家族成员，Resistin对脂肪转化具有抑制作用，故被推断是脂肪生成的一个反馈调节子或者是限制脂肪形成的一个重要信号分子。关于resistin与脂肪代谢的关系目前才刚刚起步，尤其它与脂肪分解途径的关系几乎还没有过报道。
本研究以遗传性脂肪型和瘦肉型猪作为研究对象，通过半定量RT-PCR和Western Blot等方法，首先，对不同品种，不同生长期猪脂肪组织中的TNF-α表达水平进行了研究；其二，分析了不同生长期猪脂肪组织中TNF-α受体(TNF-α receptor，TNFR)和TNF-转换酶及不同组织中TNF-转换酶表达水平的消长情况，以了解TNF-α受体和TNF-转换酶在脂肪组织中的表达模式是否与TNF-α保持一致；其三，比较了限食条件下，mTNF-α，sTNF-α和TACE在脂肪型猪脂肪组织中的表达差异，以研究它们三者之间及它们与脂肪沉积之间的关系；其四，为了了解Resistin在猪体内表达的特征，本研究从mRNA和蛋白质水平上研究了不同生长
期遗传脂肪型和瘦肉型猪脂肪组织中Reaistin的表达水平差异;其五,为了研究
Resistin与脂肪沉积的关系,本研究分析了不同的限食时间猪脂肪组织中Resistin
水平的变化;其六,为了确定TNF一a和Resistin是否可能通过cAMP路径参与脂
肪分解的调节,本研究对食物限制少R)或饱食(Contr01)猪血液和脂肪中一些脂肪
分解相关的参数进行了检测;最后,本研究分析了Resistin在猪脂肪组织中细胞表
达分布。
根据研究的实验结果,得出以下几个结论:l)m介吓一a,sTNF一a,TACE和
Resistin在猪脂肪组织中都有表达,而且它们的表达水平与脂肪沉积成正比;2)脂
肪沉积的减少导致了TNF一a和Resistin水平及一些脂肪分解相关参数的减少,表
明这两个脂肪细胞因子与脂肪分解途径存在着可能的关系;3) TACE可能调控着
mTNF一a和s翎F一a之间的比率;4) Resistin不仅在脂肪细胞中表达,而且还在其它
细胞型中表达,暗示了Resistin可能还具有除调节脂肪代谢以外的其它生物学活
性。
关键词脂肪组织TNF一a resistin表达与调控脂肪分解细胞分布
Adipose tissue has long been considered to be a passive, inactive tissue. However, it is now widely accepted that adipose tissue secretes a number of peptide hormones including leptin, tumor necrosis factor-alpha (TNF-α), adiponectin and resistin etc, which affect insulin action and energy homeostasis. These newly discovered functions have changed our view that adipose tissue is no longer considered only as an energy storage tissue but as a major endocrine organ.TNF-α is a multifunctional cytokine. TNF-α exists as a 26kDa membrane-bound precursor(mTNF-α), which can be processed at the cell surface by a TNF-α-converting enzyme (TACE) to genernate a 17-kDa soluble form (sTNF-α). Much effort has been focused recently on understanding the role of tumor necrosis factor-a (TNF-α) in regulating fat metabolism and insulin action in rodents and humans, however, there are few reports in domestic animals. Furthermore, to my knowledge, previous few studies distinguished the functions of mTNF-α from that of sTNF-α.Resistin is a member of the newjy discovered cysteine-rich secretory protein family. Some studies demonstrated that resistin had an inhibitory effect on adipose conversion. Therefore, resistin is speculated to be a feedback regulator of adipogenesis and a signal to restrict adipose tissue formation. It is just a start about the study of resistin actions, in particular about the relationship between resistin and lipolysis pathway.In the present study, we employ genetically obese and lean pigs as subjects. Through semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting analysis, we performed the following studies: firstly, we determined the levels of TNF-a expression in adipose tissue of different growth-stage genetically lean and obese pigs; secondly, to analyze whether the expression pattern
between TNF-α receptor (TNFR) or TACE and TNF-α is consistent or not, we examined the levels of TNF-α receptor (TNFR) and TACE in adipose tissue or other tissues from different growth-stage pigs; thirdly, to study the relationship among mTNF-α, sTNF-α and TACE as well as the relationship between them and fat deposition, we analyzed the changes of the levels of mTNF-α, sTNF-α and TACE in adipose tissue from feeding-restricted group(FR) and control group(C); fourthly, to know the characteristic of resistin expression in pigs, we determined the levels of resistin mRNA and protein in adipose tissue of different growth-stage genetically lean and obese pigs; fifthly, to understand the relationship between resistin and fat deposition, we examined the adipose amount of resistin at different time points of feeding restriction for pigs;sixthly, to know whether TNF-α and resistin regulate lipolysis via cAMP pathway, we analyzed the variations of TNF-α and resistin as well as some parameters associated with lipolysis pathway after body-weight reduction in feeding-restricted obese pigs; finally, we localized resistin expression in the cell types from pig adipose tissue.On basis of the results of our experiments, we draw a few following conclusions: 1) TNF-α, TNFR, TACE and resistin could be expressed in adipose tissue of pigs, furthermore, the levels of their expression were positively associated with fat deposition; 2) The decrease of fat deposition result in the reduction of TNF-α and resistin as well as some parameters associated with lipolysis pathway, suggesting the possible association between the two adipocytekines and lipolysis pathway; 3) TACE might play the important regulation in the ratio of mTNF-α to sTNF-α; 4) resistin was expessed not only in adipocytes but also in non-fat cells, indicating other biology actions of resistin.
引文
1. Wame JP. Tumor necrosis factor a: a key regulator of adipose tissue mass. J. Endocrinology 2003; 177: 351-355.
2. Ron F. Morrison and Stephen R. Farmer role of PPARy in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18 (INK4c) and p21(Wafl/Cipl), during adipogenesis. J. Biol. Chem. 1999; 274:17088-17097.
3. Hwang CS, Mandrup S, MacDougald OA, Geiman DE, Lane MD. Transcriptional activation of the mouse obese (ob) gene by CCAAT/enhancer binding protein alpha. Proc Natl Acad Sci U S A. 1996;93: 873-877.
4. Kaestner KH, Christy RJ, Lane MD. Mouse insulin-responsive glucose transporter gene: characterization of the gene and trans-activation by the CCAAT/enhancer binding protein. Proc Natl Acad Sci U S A. 1990; 87: 251-255.
5. McKeon C, Pham T. Transactivation of the human insulin receptor gene by the CAAT/enhancer binding protein. Biochem Biophys Res Commun. 1991,174: 721-728.
6. Tanaka T, Yoshida N, Kishimoto T, Akira S. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J. 1997; 16: 7432-7443.
7. Wu Z, Xie Y, Bucher NL, Farmer SR. Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesis. Genes Dev. 1995; 9: 2350-2363.
8. Yeh WC, Cao Z, Classon M, McKnight SL. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev. 1995; 9: 168-181.
9. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990; 347: 645-650.
10. Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, Lemberger T, Wahli W, Burger AG, Meier CA. Peroxisome Proliferator-activated Receptor Mediates Cross-talk with Thyroid Hormone Receptor by Competition for Retinoid X Receptor. J. Biol. Chem. 1995; 270: 18117-18122.
11. Gottlicher M, Widmark E, Li Q, Gustafsson JA. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci U S A. 1992; 89: 4653-4657.
12. Fajas L, Fruchart JC, Auwerx J. PPARgamma mRNA: a distinct PPARgamma mRNA subtype transcribed from an independent promoter. FEBS Lett. 1998; 438: 55-60.
13. Altiok S, Xu M, Spiegelman BM. PPARgamma induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A. Genes Dev. 1997; 11: 1987-1998.
14. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 1996; 271: 10697-10703.
15. Tontonoz P, Hu E, Spiegelman BM. Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma. Curr Opin Genet Dev. 1995; 5: 571-576.
16. Brun RP, Tontonoz P, Forman BM, Ellis R, Chen J, Evans RM, Spiegelman BM. Differential activation of adipogenesis by multiple PPAR isoforms. Genes Dev. 1996; 10:974-984.
17. Kim JB, Spotts GD, Halvorsen YD, Shih HM, Ellenberger T, Towle HC, Spiegelman BM. Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix-loop-helix domain. Mol Cell Biol. 1995; 15: 2582-2588.
18. Kim JB, Spiegelman BM. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev. 1996; 10: 1096-107.
19. Kim JB, Wright HM, Wright M, Spiegelman BM. ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand. Proc Natl Acad Sci U S A. 1998; 95:4333-4337.
20. Zhou YT, Wang ZW, Higa M, Newgard CB, Unger RH. Reversing adipocyte differentiation: implications for treatment of obesity. Proc Natl Acad Sci U S A. 1999; 96:2391-2395.
21. Hotamisligil GS. The role of TNF-a and TNF receptor in obesity and insulin resistance. J Intern Med 1999; 245: 621-625.
22. Friedman JM. Obesity in the new millennium. Nature 2000; 404:632-634.
23. Yamauchi T, Kamon J, Waki H et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941-946.
24. Mohamed-Ali V, Goodrick S, Rawesh A et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997; 82: 4196-4200.
25. Morange P.E., Lijnen H.R., Alessi M.C., Kopp F., Collen D., Juhan-Vague I. Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet- induced obesity. Arterioscler Thromb Vase Biol. 2000; 20: 1150-1154.
26. Steppan CM, Bailey ST, Bhat S et al. The hormone resistin links obesity to diabetes. Nature 2001; 409:307-312.
27. Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab. 2000; 11: 212-217.
28. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin- 6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001; 280: E745-E751.
29. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995; 95: 2111-2119.
30. Okuno A, Tamemoto H, Tobe K et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest. 1998; 101: 1354-1361.
31. Sewter CP, Digby JE, Blows F, Prins J, O' Rahilly S. Regulation of tumour necrosisfactor-alpha release from human adipose tissue in vitro. J Endocrinol. 1999; 163: 33-38.
32. Orban Z, Remaley AT, Sampson M, Trajanoski Z, Chrousos GP. The differential effect of food intake and beta-adrenergic stimulation on adipose-derived hormones and cytokines in man. J Clin Endocrinol Metab. 1999; 84: 2126-2133.
33. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 1996; 274:1377-1379.
34. Zilberfarb V, Siquier K, Strosberg AD, Issad T. Effect of dexamethasone on adipocyte differentiation markers and tumour necrosis factor-alpha expression in human PAZ6 cells. Diabetologia 2001; 44: 377-386.
35. Chen XL, Lee K, Hartzell DL et al. Adipocyte insensitivity to insulin in growth hormone-transgenic mice. Biochem Biophys Res Commun. 2001; 283: 933-937.
36. Ikeda A, Chang KT, Matsumoto Y et al. Obesity and insulin resistance in human growth hormone transgenic rats. Endocrinology 1998; 139: 3057-3063.
37. Bulow B, Ahren B, Erfurth EM Increased leptin and tumour necrosis factor alpha per unit fat mass in hypopituitary women without growth hormone treatment. Eur J Endocrinol. 2001; 145: 737-742.
38. Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res. 2001; 9: 414-417.
39. Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 1997; 40: 1286-1292.
40. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327-334.
41. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106: 679-684.
42. Fasshauer M, Klein J, Lossner U, Paschke R. Interleukin (IL)-6 mRNA expression is stimulated by insulin, isoproterenol, tumour necrosis factor alpha, growth hormone, and IL-6 in 3T3-L1 adipocytes. Horm Metab Res. 2003; 35: 147-152.
43. Mohamed-Ali V, Flower L, Sethi J et al. beta- Adrenergic regulation of IL-6 release from adipose tissue: in vivo and in vitro studies. J Clin Endocrinol Metab 2001; 86: 5864-5869.
44. Path G, Bornstein SR, Gurniak M, Chrousos GP, Scherbaum WA, Hauner H. Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function. J Clin Endocrinol Metab 2001; 86:2281-2288.
45. Vicennati V, Vottero A, Friedman C, Papanicolaou DA. Hormonal regulation of interleukin-6 production in human adipocytes. Int J Obes Relat Metab Disord 2002; 26: 905-911.
46. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998; 83: 847-850.
47. Papanicolaou DA, Petrides JS, Tsigos C et al. Exercise stimulates interleukin-6 secretion: inhibition by glucocorticoids and correlation with catecholamines. Am J Physiol 1996; 271: E601-E605.
48. Sesmilo G, Biller BM, Llevadot J et al. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intem Med 2000; 133:111-122.
49. Grunfeld C, Feingold KR The metabolic effects of tumor necrosis factor and other cytokines. Biotherapy 1991; 3: 143-158.
50. Janke J, Engeli S, Gorzelniak K, Luft FC, Sharma AM. Resistin gene expression in human adipocytes is not related to insulin resistance. Obes Res. 2002; 10: 1-5.
51. Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun 2001; 285: 561-564.
52. Way JM, Gorgun CZ, Tong Q et al. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 2001; 276: 25651-25653.
53. Le Lay S, Boucher J, Rey A et al. Decreased resistin expression in mice with different sensitivities to a highfat diet. Biochem Biophys Res Commun. 2001; 289:
54. Juan CC, Au LC, Fang VS et al. Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids. Biochem Biophys Res Commun 2001; 289:1328-1333.
55. Milan G, Granzotto M, Scarda A et al. Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss. Obes Res 2002; 10: 1095-1103.
56. Fukui Y, Motojima K Expression of resistin in the adipose tissue is modulated by various factors including peroxisome proliferator-activated receptor alpha. Diabetes Obes Metab 2002; 4: 342-345.
57. Shojima N, Sakoda H, Ogihara T et al. Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes 2002; 51:1737-1744.
58. Haugen F, Jorgensen A, Drevon CA, Trayhurn P. Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes. FEBS Lett. 2001; 507:105-108.
59. Moore GB, Chapman H, Holder JC et al. Differential regulation of adipocytokine mRNAs by rosiglitazone in db/db mice. Biochem Biophys Res Commun 2001; 286: 735-741.
60. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Isoproterenol inhibits resistin gene expression through a G(S)-protein-coupled pathway in 3T3-L1 adipocytes. FEBS Lett 2001; 500: 60-63.
61. Kim KH, Lee K, Moon YS, Sul HS. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem 2001; 276: 11252-11256.
62. Zhong Q, Lin CY, Clarke KJ, Kemppainen RJ, Schwartz DD, Judd RL. Endothelin-1 inhibits resistin secretion in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2002; 296: 383-387.
63. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2001; 288: 1027-1031.
64. Delhanty PJ, Mesotten D, McDougall F, Baxter RC. Growth hormone rapidly induces resistin gene expression in white adipose tissue of spontaneous dwarf (SDR) rats. Endocrinology 2002; 143: 2445-2448.
65. Weyer C, Funahashi T, Tanaka S et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86: 1930-1935.
66. Hotta K, Funahashi T, Arita Y et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20: 1595-1599.
67. Maeda N, Takahashi M, Funahashi T et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001; 50: 2094-2099.
68. Yu JG, Javorschi S, Hevener AL et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 2002; 51: 2968-2974.
69. Motoshima H, Wu X, Sinha MK et al. Differential regulation of adiponectin secretion from cultured human omentai and subcutaneous adipocytes: effects of insulin and rosiglitazone. J Clin Endocrinol Metab 2002; 87: 5662-5667.
70.Yang WS, Jeng CY, Wu TJ et al. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 2002; 25: 376-380.
71. Combs TP, Wagner JA, Berger J et al. Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology 2002; 143: 998-1007.
72. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Adiponectin gene expression is inhibited by beta- adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes. FEBS Lett 2001; 507: 142-146.
73. Delporte ML, Funahashi T, Takahashi M, Matsuzawa Y, Brichard SM. Pre- and post- translational negative effect of beta-adrenoceptor agonists on adiponectin secretion: in vitro and in vivo studies. Biochem J 2002; 367: 677-685.
74. Fasshauer M, Kralisch S, Klier M et al. Adiponectin gene expression and secretion is inhibited by interleukin- 6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2003; 301:1045-1050.
75. Kappes A, Loffler G. Influences of ionomycin, dibutyryl- cycloAMP and tumour necrosis factor-alpha on intracellular amount and secretion of apMl in differentiating primary human preadipocytes. Horm Metab Res 2000; 32: 548-554.
76. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2002; 290:1084-1089.
77. Halleux CM, Takahashi M, Delporte ML et al. Secretion of adiponectin and regulation of apMl gene expression in human visceral adipose tissue. Biochem Biophys Res Commun 2001; 288: 1102-1107.
78. Makimura H, Mizuno TM, Bergen H, Mobbs CV. Adiponectin is stimulated by adrenalectomy in ob/ob mice and is highly correlated with resistin mRNA. Am J Physiol Endocrinol Metab 2002; 283: E1266-E1271.
79. Masuzaki H, Paterson J, Shinyama H et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001; 294: 2166-2170.
80. Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000; 62:413-437.
81. Kellerer M, Lammers R, Fritsche A et al. Insulin inhibits leptin receptor signalling in HEK293 cells at the level of janus kinase-2: a potential mechanism for hyperinsulinaemia- associated leptin resistance. Diabetologia 2001; 44: 1125-1132.
82. Femandez-Galaz C, Fernandez-Agullo T, Perez C et al. Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats. Diabetologia 2002; 45: 997-1003.
83. Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000; 11: 327-332.
84. Zhang B, Graziano MP, Doebber TW et al. Downregulation of the expression of the obese gene by an antidiabetic thiazolidinedione in Zucker diabetic fatty rats and db/db mice. J Biol Chem 1996; 271: 9455-9459.
85. Kallen CB, Lazar MA. Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes. Proc Natl Acad Sci USA 1996; 93: 5793-5796.
86. De Vos P, Lefebvre AM, Miller SG et al. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J Clin Invest. 1996; 98: 1004-1009.
87. Mantzoros CS, Qu D, Frederich RC, Susulic VS et al. Activation of beta(3) adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 1996; 45:909-914.
88. Slieker LJ, Sloop KW, Surface PL et al. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem 1996; 271: 5301-5304
89. Rentsch J, Chiesi M. Regulation of ob gene mRNA levels in cultured adipocytes. FEBS Lett 1996; 379: 55-59.
90. Hardie LJ, Rayner DV, Holmes S, Trayhurn P. Circulating leptin levels are modulated by fasting, cold exposure and insulin administration in lean but not Zucker (fa/fa) rats as measured by ELISA. Biochem Biophys Res Commun 1996; 223: 660-665.
91. Saladin R, De Vos P, Guerre-Millo M et al. Transient increase in obese gene expression after food intake or insulin administration. Nature 1995; 377: 527-529.
92. De Vos P, Saladin R, Auwerx J, Staels B. Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J Biol Chem 1995; 270:15958-15961.
93. Asada N, Takahashi Y, Honjo M. Effects of 22K or 20K human growth hormone on lipolysis, leptin production in adipocytes in the presence and absence of human growth hormone binding protein. Horm Res 2000; 54: 203-207.
94. Norrelund H, Gravholt CH, Englaro P et al. Increased levels but preserved diurnal variation of serum leptin in GH-deficient patients: lack of impact of different modes of GH administration. Eur J Endocrinol 1998; 138: 644-652.
95. Brennan BM, Rahim A, Blum WF, Adams JA, Eden OB, Shalet SM. Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity? Clin Endocrinol (Oxf) 1999; 50: 163-169.
96. Miyakawa M, Tsushima T, Murakami H, Isozaki O, Demura H, Tanaka T. Effect of growth hormone (GH) on serum concentrations of leptin: study in patients with acromegaly and GH deficiency. J Clin Endocrinol Metab 1998; 83: 3476-3479.
97. Damjanovic SS, Petakov MS, Raicevic S et al. Serum leptin levels in patients with acromegaly before and after correction of hypersomatotropism by transsphenoidal surgery. J Clin Endocrinol Metab 2000; 85: 147-154.
98. Sethi JK, Hotamisligil GS. The role of TNF-a in adipocyte metabolism. Cell & Developmental Biology 1999; 10:19-29.
99. Peraldi P, Hotamisligil GS, Buurman WA, Whitei MF, Spiegelman BM. Tumor necrosis factor (TNF)-a inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. Biochemistry and Molecular Biology 1996; 271:13018-13022.
100. Heller RA, Kronke M. Tumor necrosis factor receptor-mediated signaling pathways. J Cell Biol. 1994; 126: 5-9.
101. Moss, M. L., Jin, S. L., Milla, M. E., Burkhart, W., Carter, H. L., Chen, W. J., et.al. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 1997; 385:733-736.
102. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, et.al A metalloproteinase disintegrin that releases tumour-necrosis factor- alpha from cells. Nature 1997; 385:729-33.
103. Lunn CA, Fan X, Dalie B, et al. Purification of ADAM 10 from bovine spleen as a TNF-a convertase. FEBS Lett. 1997; 400: 333-335.
104. Fargeas MJ, Fioramonti J, Bueno L. Central action of interleukin 1-beta on intestinal motility in rats: mediation by two mechanism. Castroenterology 1993; 104: 377-383.
105. Frederich RC, Hamann A, Anderson S etal. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nature Med. 1995; 1: 1311-1314.
106. Kirchgessner TG, Uysal KT, Wiesbrock SM etal. Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J. Clin. Invest. 1997; 100: 2777-2782.
107. Ranganathan S, maffei M, Kern PA. Adipose tissue ob mRNA expression in humans: discordance with plasma leptin and relationship with adipose TNF-alpha expression. J Lipid Res. 1998; 39: 724-730.
108. Stephens JM, Lee J, Pilch PF. Tumor necrosis factor alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and Glut4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem 1997; 272: 971-976.
109. Stephens JM, Pekala PH. Transcriptional repression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. J Biol. Chem. 1991; 266: 21839-21845.
110. Jain R, Police S, Phelps K et al. Tumor necrosis factor-alpha regulates expression of the CCAAT-enhancer-binding proteins(C/EBPs) and determines the occupation of the C/EBP site in the promoter of the insulin-responsive glucose-transporter gene in 3T3-L1 adipocytes. Biochem J. 1999; 338: 737-743.
111. Jain R, Phelps K, Pekala PH. Tumor necrosis factor-alpha initiated signal transduction in 3T3-L1 adipocytes. J Cell Physiol. 1999; 179: 58-66.
112. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91.
113. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1 -mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance. Science 1996; 271: 665-668.
114. Saltiel AR. You are what you secrete. Nature Med. 2001,7: 887 - 888.
115. Banerjee RR, Lazar MA. Dimerization of resistin and resistin-like molecules is determined by a single cysteine. J Bio Chem. 2001; 276: 5970-5973.
116. Steppan CM, Lazar MA. Resistin and obesity-associated insulin resistance. Trens Endocrino Metabolism. 2002; 13: 18-23.
117. Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab. 2002; 13: 84-89.
118. F Her JS. The missing link with obesity? Nature 2001; 409: 292-293.
119. Savage DB, Sewter CP, Klenk ES, et al. Resistin/Fizz3 expression in relation to obesity and Peroxisome Proliferator-Activated Receptor-y action in humans. Diabetes 2001; 50: 2199-2202.
120. Peterson GL. A simplification of the protein assay method of Lowry et al., which is more generally applicable. Anal Biochem.1977; 83:346-356.
121. Xu H, Sethi JK, Hotamisligil GS: Transmembrane tumor necrosis factor (TNF)-alpha inhibits adipocyte differentiation by selectively activating TNF receptor 1.J Biol Chem 1999; 274: 26287-26895.
122. Rodbell M. Metabolism of isolated fat cells-effect of hormones on glucose metabolism and lipolysis. J Biol Chem 1964; 239: 375-380.
123. Mohamed-Ali V, Pinkney JH & Coppack SW. Adipose tissue as an endocrine and paracrine organ. Int J Obes 1998; 22: 1145-1158.
124. Lopezsoriano J, Llovera M, Carbo N, Garciamartinez C, Lopezsoriano FJ, Argiles JM. Lipid metabolism in tumor-bearing mice-studies with knockout mice for tumor necrosis factor receptor 1 protein. Mol Cell Endocrinol 1997; 132: 93-99.
125．J．萨姆布鲁克，E．F．费里奇，T．曼尼阿蒂斯．金冬雁，黎孟枫等译．分子克隆实验指南(第二版)北京：科学出版社，1998：PP：881-885．
126．F．奥斯伯，R．金斯顿，T．塞德曼等著．颜子颖，王海林译．精编分子生物学实验指南北京：科学出版社，1998：PP：371-373．
127. Hotamisligil GS, Spiegelman BM: Tumor necrosis factor-a: A key component of the obesity diabetes link. Diabetes 1994; 43: 1271-1278.
128. Hotamisligil GS, Amer P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest. 1995; 95: 2409-2415.
129. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-a function. Nature. 1997; 389:610-614.
130. Bluher M, Kratzsch J, Paschke R. Plasma levels of tumor necrosis factor-alpha;angiotensin Ⅱ, growth hormone, and IGF-Ⅰ are not elevated in insulin-resistant obese individuals with impaired glucose tolerance. Diabetes Care 2001; 24: 328-334.
131. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R: Effects of engineered human anti-TNF-_ antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 1996; 45:881-885.
132. Dandona P, Weinstock R, Thusu K, Abdel- Rahman E, Aljada A, Wadden T: Tumor necrosis factor-a in sera of obese patients: Fall with weight loss. J Clin Endocrinol Metab 1998; 83: 2907-2910.
133. Hauner H, Bender M, Haastert B, Hube F: Plasma concentrations of soluble TNF-alpha receptors in obese subjects. Int J Obes Relat Metab Disord 1998; 22: 1239-1243.
134. Boeck MA, Chen C, Cunningham-Rundles S. Altered immune function in a morbidly obese pediatric population. Ann NY Acad Sci 1993; 699:253- 256.
135. Xu H, Uysal KT, Becherer JD, Arner P, Hotamisligil GS. Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity. Diabetes 2002; 51: 1876-1883.
136. Voros G, Maquoi E, Collen D, Lijnen HR. Differential expression of plasminogen activator inhibitor-1, tumor necrosis factor-a, TNF-a converting enzyme and ADAMTS family members in murine fat territories. Biochimica et Biophysica Acta. 2003; 1625: 36-42.
137. Morimoto Y, Nishikawa K, Ohashi M. KB-R7785, a novel matrix metalloproteinase inhibitor, exerts its antidiabetic effect by inhibiting tumor necrosis factor-a production. Life Science 1997; 61: 795-803.
138. Togashi N, Ura N, Higashiura K, Murakami H, Shimamoto K. Effect of TNF-a-converting enzyme inhibitor on insulin resistance in fructose-fed rats. Hypertension 2002; 39: 578-580.
139. Carbo N, Costelli P, Tessitore L et al. Anti-tumour necresis factor-alpha treatment interferes with changes in lipid metabolism in a cachectic tumor model. Clin Sci 1994; 87: 349-355
140. Ramsay TG Fat cells. Endocrinol Metab Clin North Am 1996; 25: 847-870.
141. Green A, Dobias SB, Walters DJ, Brasier AR. Tumor necresis factor increases the rate of lipolysis in primary cultures of adipocytes without altering levels of hormone-sensitive lipase. Endocrinology 1994; 134: 2581-2588.
142. Souza SC, Yamamoto MT, Franciosa MD, Lien P, Greenberg AS. BRL 49653 blocks the lipolytic actions of tumor necresis factor-alpha: a potential new insulin- sensitizing mechanism for thiazolidinediones. Diabetes 1998; 47: 691-695.
14
143. Rajala MW, Obici S, Scherer PE, Rossetti LAdipose-derived resistin and gut-derived resistin-like molecule-β selectively impair insulin action on glucose production. J Clin Invest. 2003; 111: 225-230.
144．杨在清，马志科，孙超等．猪脂肪沉积的品系差异及其cAMP的调控作用。畜牧兽医学报1996；27：489-494．
145. Miles PD, Romeo OM, Higo K, Cohen A, Rafaat K, Olefsky JM. TNF-alphainduced insulin resistance in vivo and its prevention by troglitazone. Diabetes 1997; 46:1678-1683.
146. Uysal KT, Wiesbrock SM, Hotamisligil GS. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity.Endocrinology 1998; 139: 4832-4838.
147. Fujita H, Fujishima H, Morii T, et al. Effect of metformin on adipose tissue resistin expression in db/db mice. Biochem Biophys Res Commun. 2002; 298:345-349.
148. Bruun JM, Verdich C, Toubro S, Astrup A, Richelsen B. Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleuldn-6 and tumor necrosis factor-alpha. Effect of weight loss in obese men. Eur J Endocrinol 2003;148:535-542.
149. Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan. G. Adipenectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 2003; 52:1779-1785.
150. Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab 1998; 83:2907-2910.
151. Steffen DG, Arakelian MC, Phinney G, Brown LJ, Mersmann HJ. Effect of nutritional status on swine adipose tissue lipolytic activities. J Anim Sci 1981; 52:1306-1311.
152. Mersmann HJ, McNeil MD. Lipid mobilization by obese and lean pigs infused with the beta-adrenergic agonist isoproterenol. J Anim Sci 1989; 67:1992-1996.
153. McNeel RL, Ding ST, Smith EO, Mersmann HJ. Effect of feed restriction on adipose tissue transcript concentrations in genetically lean and obese pigs. J Anim Sci 2000; 78: 934-942.
154. Mersmann HJ, Koong LJ. Effect of plane of nutrition on adipose tissue lipid metabolism in genetically obese and lean pigs. J Nutr 1984; 114:862-868.
155. Gasic S, Tian B, Green A. Tumor necrosis factor-alpha stimulates lipolysis in adipocytes by decreasing Gj protein concentrations. J Biol Chem 1999; 274: 6770 -6775.
156. Zhang HH, Halbleib M, Ahmad F, Manganiello VC, Greenberg AS. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 2002; 51: 2929-2935.
157. Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M. Resistin release by human adipose tissue explants in primary culture. Biochem Biophys Res Commun 2003; 300: 674-678.
2. Ron F. Morrison and Stephen R. Farmer role of PPARy in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18 (INK4c) and p21(Wafl/Cipl), during adipogenesis. J. Biol. Chem. 1999; 274:17088-17097.
3. Hwang CS, Mandrup S, MacDougald OA, Geiman DE, Lane MD. Transcriptional activation of the mouse obese (ob) gene by CCAAT/enhancer binding protein alpha. Proc Natl Acad Sci U S A. 1996;93: 873-877.
4. Kaestner KH, Christy RJ, Lane MD. Mouse insulin-responsive glucose transporter gene: characterization of the gene and trans-activation by the CCAAT/enhancer binding protein. Proc Natl Acad Sci U S A. 1990; 87: 251-255.
5. McKeon C, Pham T. Transactivation of the human insulin receptor gene by the CAAT/enhancer binding protein. Biochem Biophys Res Commun. 1991,174: 721-728.
6. Tanaka T, Yoshida N, Kishimoto T, Akira S. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J. 1997; 16: 7432-7443.
7. Wu Z, Xie Y, Bucher NL, Farmer SR. Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesis. Genes Dev. 1995; 9: 2350-2363.
8. Yeh WC, Cao Z, Classon M, McKnight SL. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev. 1995; 9: 168-181.
9. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990; 347: 645-650.
10. Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, Lemberger T, Wahli W, Burger AG, Meier CA. Peroxisome Proliferator-activated Receptor Mediates Cross-talk with Thyroid Hormone Receptor by Competition for Retinoid X Receptor. J. Biol. Chem. 1995; 270: 18117-18122.
11. Gottlicher M, Widmark E, Li Q, Gustafsson JA. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci U S A. 1992; 89: 4653-4657.
12. Fajas L, Fruchart JC, Auwerx J. PPARgamma mRNA: a distinct PPARgamma mRNA subtype transcribed from an independent promoter. FEBS Lett. 1998; 438: 55-60.
13. Altiok S, Xu M, Spiegelman BM. PPARgamma induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A. Genes Dev. 1997; 11: 1987-1998.
14. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 1996; 271: 10697-10703.
15. Tontonoz P, Hu E, Spiegelman BM. Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma. Curr Opin Genet Dev. 1995; 5: 571-576.
16. Brun RP, Tontonoz P, Forman BM, Ellis R, Chen J, Evans RM, Spiegelman BM. Differential activation of adipogenesis by multiple PPAR isoforms. Genes Dev. 1996; 10:974-984.
17. Kim JB, Spotts GD, Halvorsen YD, Shih HM, Ellenberger T, Towle HC, Spiegelman BM. Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix-loop-helix domain. Mol Cell Biol. 1995; 15: 2582-2588.
18. Kim JB, Spiegelman BM. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev. 1996; 10: 1096-107.
19. Kim JB, Wright HM, Wright M, Spiegelman BM. ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand. Proc Natl Acad Sci U S A. 1998; 95:4333-4337.
20. Zhou YT, Wang ZW, Higa M, Newgard CB, Unger RH. Reversing adipocyte differentiation: implications for treatment of obesity. Proc Natl Acad Sci U S A. 1999; 96:2391-2395.
21. Hotamisligil GS. The role of TNF-a and TNF receptor in obesity and insulin resistance. J Intern Med 1999; 245: 621-625.
22. Friedman JM. Obesity in the new millennium. Nature 2000; 404:632-634.
23. Yamauchi T, Kamon J, Waki H et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941-946.
24. Mohamed-Ali V, Goodrick S, Rawesh A et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997; 82: 4196-4200.
25. Morange P.E., Lijnen H.R., Alessi M.C., Kopp F., Collen D., Juhan-Vague I. Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet- induced obesity. Arterioscler Thromb Vase Biol. 2000; 20: 1150-1154.
26. Steppan CM, Bailey ST, Bhat S et al. The hormone resistin links obesity to diabetes. Nature 2001; 409:307-312.
27. Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab. 2000; 11: 212-217.
28. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin- 6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001; 280: E745-E751.
29. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995; 95: 2111-2119.
30. Okuno A, Tamemoto H, Tobe K et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest. 1998; 101: 1354-1361.
31. Sewter CP, Digby JE, Blows F, Prins J, O' Rahilly S. Regulation of tumour necrosisfactor-alpha release from human adipose tissue in vitro. J Endocrinol. 1999; 163: 33-38.
32. Orban Z, Remaley AT, Sampson M, Trajanoski Z, Chrousos GP. The differential effect of food intake and beta-adrenergic stimulation on adipose-derived hormones and cytokines in man. J Clin Endocrinol Metab. 1999; 84: 2126-2133.
33. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 1996; 274:1377-1379.
34. Zilberfarb V, Siquier K, Strosberg AD, Issad T. Effect of dexamethasone on adipocyte differentiation markers and tumour necrosis factor-alpha expression in human PAZ6 cells. Diabetologia 2001; 44: 377-386.
35. Chen XL, Lee K, Hartzell DL et al. Adipocyte insensitivity to insulin in growth hormone-transgenic mice. Biochem Biophys Res Commun. 2001; 283: 933-937.
36. Ikeda A, Chang KT, Matsumoto Y et al. Obesity and insulin resistance in human growth hormone transgenic rats. Endocrinology 1998; 139: 3057-3063.
37. Bulow B, Ahren B, Erfurth EM Increased leptin and tumour necrosis factor alpha per unit fat mass in hypopituitary women without growth hormone treatment. Eur J Endocrinol. 2001; 145: 737-742.
38. Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res. 2001; 9: 414-417.
39. Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 1997; 40: 1286-1292.
40. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327-334.
41. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106: 679-684.
42. Fasshauer M, Klein J, Lossner U, Paschke R. Interleukin (IL)-6 mRNA expression is stimulated by insulin, isoproterenol, tumour necrosis factor alpha, growth hormone, and IL-6 in 3T3-L1 adipocytes. Horm Metab Res. 2003; 35: 147-152.
43. Mohamed-Ali V, Flower L, Sethi J et al. beta- Adrenergic regulation of IL-6 release from adipose tissue: in vivo and in vitro studies. J Clin Endocrinol Metab 2001; 86: 5864-5869.
44. Path G, Bornstein SR, Gurniak M, Chrousos GP, Scherbaum WA, Hauner H. Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function. J Clin Endocrinol Metab 2001; 86:2281-2288.
45. Vicennati V, Vottero A, Friedman C, Papanicolaou DA. Hormonal regulation of interleukin-6 production in human adipocytes. Int J Obes Relat Metab Disord 2002; 26: 905-911.
46. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998; 83: 847-850.
47. Papanicolaou DA, Petrides JS, Tsigos C et al. Exercise stimulates interleukin-6 secretion: inhibition by glucocorticoids and correlation with catecholamines. Am J Physiol 1996; 271: E601-E605.
48. Sesmilo G, Biller BM, Llevadot J et al. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intem Med 2000; 133:111-122.
49. Grunfeld C, Feingold KR The metabolic effects of tumor necrosis factor and other cytokines. Biotherapy 1991; 3: 143-158.
50. Janke J, Engeli S, Gorzelniak K, Luft FC, Sharma AM. Resistin gene expression in human adipocytes is not related to insulin resistance. Obes Res. 2002; 10: 1-5.
51. Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun 2001; 285: 561-564.
52. Way JM, Gorgun CZ, Tong Q et al. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 2001; 276: 25651-25653.
53. Le Lay S, Boucher J, Rey A et al. Decreased resistin expression in mice with different sensitivities to a highfat diet. Biochem Biophys Res Commun. 2001; 289:
54. Juan CC, Au LC, Fang VS et al. Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids. Biochem Biophys Res Commun 2001; 289:1328-1333.
55. Milan G, Granzotto M, Scarda A et al. Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss. Obes Res 2002; 10: 1095-1103.
56. Fukui Y, Motojima K Expression of resistin in the adipose tissue is modulated by various factors including peroxisome proliferator-activated receptor alpha. Diabetes Obes Metab 2002; 4: 342-345.
57. Shojima N, Sakoda H, Ogihara T et al. Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes 2002; 51:1737-1744.
58. Haugen F, Jorgensen A, Drevon CA, Trayhurn P. Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes. FEBS Lett. 2001; 507:105-108.
59. Moore GB, Chapman H, Holder JC et al. Differential regulation of adipocytokine mRNAs by rosiglitazone in db/db mice. Biochem Biophys Res Commun 2001; 286: 735-741.
60. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Isoproterenol inhibits resistin gene expression through a G(S)-protein-coupled pathway in 3T3-L1 adipocytes. FEBS Lett 2001; 500: 60-63.
61. Kim KH, Lee K, Moon YS, Sul HS. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem 2001; 276: 11252-11256.
62. Zhong Q, Lin CY, Clarke KJ, Kemppainen RJ, Schwartz DD, Judd RL. Endothelin-1 inhibits resistin secretion in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2002; 296: 383-387.
63. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2001; 288: 1027-1031.
64. Delhanty PJ, Mesotten D, McDougall F, Baxter RC. Growth hormone rapidly induces resistin gene expression in white adipose tissue of spontaneous dwarf (SDR) rats. Endocrinology 2002; 143: 2445-2448.
65. Weyer C, Funahashi T, Tanaka S et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86: 1930-1935.
66. Hotta K, Funahashi T, Arita Y et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20: 1595-1599.
67. Maeda N, Takahashi M, Funahashi T et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001; 50: 2094-2099.
68. Yu JG, Javorschi S, Hevener AL et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 2002; 51: 2968-2974.
69. Motoshima H, Wu X, Sinha MK et al. Differential regulation of adiponectin secretion from cultured human omentai and subcutaneous adipocytes: effects of insulin and rosiglitazone. J Clin Endocrinol Metab 2002; 87: 5662-5667.
70.Yang WS, Jeng CY, Wu TJ et al. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 2002; 25: 376-380.
71. Combs TP, Wagner JA, Berger J et al. Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology 2002; 143: 998-1007.
72. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Adiponectin gene expression is inhibited by beta- adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes. FEBS Lett 2001; 507: 142-146.
73. Delporte ML, Funahashi T, Takahashi M, Matsuzawa Y, Brichard SM. Pre- and post- translational negative effect of beta-adrenoceptor agonists on adiponectin secretion: in vitro and in vivo studies. Biochem J 2002; 367: 677-685.
74. Fasshauer M, Kralisch S, Klier M et al. Adiponectin gene expression and secretion is inhibited by interleukin- 6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2003; 301:1045-1050.
75. Kappes A, Loffler G. Influences of ionomycin, dibutyryl- cycloAMP and tumour necrosis factor-alpha on intracellular amount and secretion of apMl in differentiating primary human preadipocytes. Horm Metab Res 2000; 32: 548-554.
76. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2002; 290:1084-1089.
77. Halleux CM, Takahashi M, Delporte ML et al. Secretion of adiponectin and regulation of apMl gene expression in human visceral adipose tissue. Biochem Biophys Res Commun 2001; 288: 1102-1107.
78. Makimura H, Mizuno TM, Bergen H, Mobbs CV. Adiponectin is stimulated by adrenalectomy in ob/ob mice and is highly correlated with resistin mRNA. Am J Physiol Endocrinol Metab 2002; 283: E1266-E1271.
79. Masuzaki H, Paterson J, Shinyama H et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001; 294: 2166-2170.
80. Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000; 62:413-437.
81. Kellerer M, Lammers R, Fritsche A et al. Insulin inhibits leptin receptor signalling in HEK293 cells at the level of janus kinase-2: a potential mechanism for hyperinsulinaemia- associated leptin resistance. Diabetologia 2001; 44: 1125-1132.
82. Femandez-Galaz C, Fernandez-Agullo T, Perez C et al. Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats. Diabetologia 2002; 45: 997-1003.
83. Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000; 11: 327-332.
84. Zhang B, Graziano MP, Doebber TW et al. Downregulation of the expression of the obese gene by an antidiabetic thiazolidinedione in Zucker diabetic fatty rats and db/db mice. J Biol Chem 1996; 271: 9455-9459.
85. Kallen CB, Lazar MA. Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes. Proc Natl Acad Sci USA 1996; 93: 5793-5796.
86. De Vos P, Lefebvre AM, Miller SG et al. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J Clin Invest. 1996; 98: 1004-1009.
87. Mantzoros CS, Qu D, Frederich RC, Susulic VS et al. Activation of beta(3) adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 1996; 45:909-914.
88. Slieker LJ, Sloop KW, Surface PL et al. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem 1996; 271: 5301-5304
89. Rentsch J, Chiesi M. Regulation of ob gene mRNA levels in cultured adipocytes. FEBS Lett 1996; 379: 55-59.
90. Hardie LJ, Rayner DV, Holmes S, Trayhurn P. Circulating leptin levels are modulated by fasting, cold exposure and insulin administration in lean but not Zucker (fa/fa) rats as measured by ELISA. Biochem Biophys Res Commun 1996; 223: 660-665.
91. Saladin R, De Vos P, Guerre-Millo M et al. Transient increase in obese gene expression after food intake or insulin administration. Nature 1995; 377: 527-529.
92. De Vos P, Saladin R, Auwerx J, Staels B. Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J Biol Chem 1995; 270:15958-15961.
93. Asada N, Takahashi Y, Honjo M. Effects of 22K or 20K human growth hormone on lipolysis, leptin production in adipocytes in the presence and absence of human growth hormone binding protein. Horm Res 2000; 54: 203-207.
94. Norrelund H, Gravholt CH, Englaro P et al. Increased levels but preserved diurnal variation of serum leptin in GH-deficient patients: lack of impact of different modes of GH administration. Eur J Endocrinol 1998; 138: 644-652.
95. Brennan BM, Rahim A, Blum WF, Adams JA, Eden OB, Shalet SM. Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity? Clin Endocrinol (Oxf) 1999; 50: 163-169.
96. Miyakawa M, Tsushima T, Murakami H, Isozaki O, Demura H, Tanaka T. Effect of growth hormone (GH) on serum concentrations of leptin: study in patients with acromegaly and GH deficiency. J Clin Endocrinol Metab 1998; 83: 3476-3479.
97. Damjanovic SS, Petakov MS, Raicevic S et al. Serum leptin levels in patients with acromegaly before and after correction of hypersomatotropism by transsphenoidal surgery. J Clin Endocrinol Metab 2000; 85: 147-154.
98. Sethi JK, Hotamisligil GS. The role of TNF-a in adipocyte metabolism. Cell & Developmental Biology 1999; 10:19-29.
99. Peraldi P, Hotamisligil GS, Buurman WA, Whitei MF, Spiegelman BM. Tumor necrosis factor (TNF)-a inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. Biochemistry and Molecular Biology 1996; 271:13018-13022.
100. Heller RA, Kronke M. Tumor necrosis factor receptor-mediated signaling pathways. J Cell Biol. 1994; 126: 5-9.
101. Moss, M. L., Jin, S. L., Milla, M. E., Burkhart, W., Carter, H. L., Chen, W. J., et.al. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 1997; 385:733-736.
102. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, et.al A metalloproteinase disintegrin that releases tumour-necrosis factor- alpha from cells. Nature 1997; 385:729-33.
103. Lunn CA, Fan X, Dalie B, et al. Purification of ADAM 10 from bovine spleen as a TNF-a convertase. FEBS Lett. 1997; 400: 333-335.
104. Fargeas MJ, Fioramonti J, Bueno L. Central action of interleukin 1-beta on intestinal motility in rats: mediation by two mechanism. Castroenterology 1993; 104: 377-383.
105. Frederich RC, Hamann A, Anderson S etal. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nature Med. 1995; 1: 1311-1314.
106. Kirchgessner TG, Uysal KT, Wiesbrock SM etal. Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J. Clin. Invest. 1997; 100: 2777-2782.
107. Ranganathan S, maffei M, Kern PA. Adipose tissue ob mRNA expression in humans: discordance with plasma leptin and relationship with adipose TNF-alpha expression. J Lipid Res. 1998; 39: 724-730.
108. Stephens JM, Lee J, Pilch PF. Tumor necrosis factor alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and Glut4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem 1997; 272: 971-976.
109. Stephens JM, Pekala PH. Transcriptional repression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. J Biol. Chem. 1991; 266: 21839-21845.
110. Jain R, Police S, Phelps K et al. Tumor necrosis factor-alpha regulates expression of the CCAAT-enhancer-binding proteins(C/EBPs) and determines the occupation of the C/EBP site in the promoter of the insulin-responsive glucose-transporter gene in 3T3-L1 adipocytes. Biochem J. 1999; 338: 737-743.
111. Jain R, Phelps K, Pekala PH. Tumor necrosis factor-alpha initiated signal transduction in 3T3-L1 adipocytes. J Cell Physiol. 1999; 179: 58-66.
112. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91.
113. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1 -mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance. Science 1996; 271: 665-668.
114. Saltiel AR. You are what you secrete. Nature Med. 2001,7: 887 - 888.
115. Banerjee RR, Lazar MA. Dimerization of resistin and resistin-like molecules is determined by a single cysteine. J Bio Chem. 2001; 276: 5970-5973.
116. Steppan CM, Lazar MA. Resistin and obesity-associated insulin resistance. Trens Endocrino Metabolism. 2002; 13: 18-23.
117. Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab. 2002; 13: 84-89.
118. F Her JS. The missing link with obesity? Nature 2001; 409: 292-293.
119. Savage DB, Sewter CP, Klenk ES, et al. Resistin/Fizz3 expression in relation to obesity and Peroxisome Proliferator-Activated Receptor-y action in humans. Diabetes 2001; 50: 2199-2202.
120. Peterson GL. A simplification of the protein assay method of Lowry et al., which is more generally applicable. Anal Biochem.1977; 83:346-356.
121. Xu H, Sethi JK, Hotamisligil GS: Transmembrane tumor necrosis factor (TNF)-alpha inhibits adipocyte differentiation by selectively activating TNF receptor 1.J Biol Chem 1999; 274: 26287-26895.
122. Rodbell M. Metabolism of isolated fat cells-effect of hormones on glucose metabolism and lipolysis. J Biol Chem 1964; 239: 375-380.
123. Mohamed-Ali V, Pinkney JH & Coppack SW. Adipose tissue as an endocrine and paracrine organ. Int J Obes 1998; 22: 1145-1158.
124. Lopezsoriano J, Llovera M, Carbo N, Garciamartinez C, Lopezsoriano FJ, Argiles JM. Lipid metabolism in tumor-bearing mice-studies with knockout mice for tumor necrosis factor receptor 1 protein. Mol Cell Endocrinol 1997; 132: 93-99.
125．J．萨姆布鲁克，E．F．费里奇，T．曼尼阿蒂斯．金冬雁，黎孟枫等译．分子克隆实验指南(第二版)北京：科学出版社，1998：PP：881-885．
126．F．奥斯伯，R．金斯顿，T．塞德曼等著．颜子颖，王海林译．精编分子生物学实验指南北京：科学出版社，1998：PP：371-373．
127. Hotamisligil GS, Spiegelman BM: Tumor necrosis factor-a: A key component of the obesity diabetes link. Diabetes 1994; 43: 1271-1278.
128. Hotamisligil GS, Amer P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest. 1995; 95: 2409-2415.
129. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-a function. Nature. 1997; 389:610-614.
130. Bluher M, Kratzsch J, Paschke R. Plasma levels of tumor necrosis factor-alpha;angiotensin Ⅱ, growth hormone, and IGF-Ⅰ are not elevated in insulin-resistant obese individuals with impaired glucose tolerance. Diabetes Care 2001; 24: 328-334.
131. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R: Effects of engineered human anti-TNF-_ antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 1996; 45:881-885.
132. Dandona P, Weinstock R, Thusu K, Abdel- Rahman E, Aljada A, Wadden T: Tumor necrosis factor-a in sera of obese patients: Fall with weight loss. J Clin Endocrinol Metab 1998; 83: 2907-2910.
133. Hauner H, Bender M, Haastert B, Hube F: Plasma concentrations of soluble TNF-alpha receptors in obese subjects. Int J Obes Relat Metab Disord 1998; 22: 1239-1243.
134. Boeck MA, Chen C, Cunningham-Rundles S. Altered immune function in a morbidly obese pediatric population. Ann NY Acad Sci 1993; 699:253- 256.
135. Xu H, Uysal KT, Becherer JD, Arner P, Hotamisligil GS. Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity. Diabetes 2002; 51: 1876-1883.
136. Voros G, Maquoi E, Collen D, Lijnen HR. Differential expression of plasminogen activator inhibitor-1, tumor necrosis factor-a, TNF-a converting enzyme and ADAMTS family members in murine fat territories. Biochimica et Biophysica Acta. 2003; 1625: 36-42.
137. Morimoto Y, Nishikawa K, Ohashi M. KB-R7785, a novel matrix metalloproteinase inhibitor, exerts its antidiabetic effect by inhibiting tumor necrosis factor-a production. Life Science 1997; 61: 795-803.
138. Togashi N, Ura N, Higashiura K, Murakami H, Shimamoto K. Effect of TNF-a-converting enzyme inhibitor on insulin resistance in fructose-fed rats. Hypertension 2002; 39: 578-580.
139. Carbo N, Costelli P, Tessitore L et al. Anti-tumour necresis factor-alpha treatment interferes with changes in lipid metabolism in a cachectic tumor model. Clin Sci 1994; 87: 349-355
140. Ramsay TG Fat cells. Endocrinol Metab Clin North Am 1996; 25: 847-870.
141. Green A, Dobias SB, Walters DJ, Brasier AR. Tumor necresis factor increases the rate of lipolysis in primary cultures of adipocytes without altering levels of hormone-sensitive lipase. Endocrinology 1994; 134: 2581-2588.
142. Souza SC, Yamamoto MT, Franciosa MD, Lien P, Greenberg AS. BRL 49653 blocks the lipolytic actions of tumor necresis factor-alpha: a potential new insulin- sensitizing mechanism for thiazolidinediones. Diabetes 1998; 47: 691-695.
14
143. Rajala MW, Obici S, Scherer PE, Rossetti LAdipose-derived resistin and gut-derived resistin-like molecule-β selectively impair insulin action on glucose production. J Clin Invest. 2003; 111: 225-230.
144．杨在清，马志科，孙超等．猪脂肪沉积的品系差异及其cAMP的调控作用。畜牧兽医学报1996；27：489-494．
145. Miles PD, Romeo OM, Higo K, Cohen A, Rafaat K, Olefsky JM. TNF-alphainduced insulin resistance in vivo and its prevention by troglitazone. Diabetes 1997; 46:1678-1683.
146. Uysal KT, Wiesbrock SM, Hotamisligil GS. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity.Endocrinology 1998; 139: 4832-4838.
147. Fujita H, Fujishima H, Morii T, et al. Effect of metformin on adipose tissue resistin expression in db/db mice. Biochem Biophys Res Commun. 2002; 298:345-349.
148. Bruun JM, Verdich C, Toubro S, Astrup A, Richelsen B. Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleuldn-6 and tumor necrosis factor-alpha. Effect of weight loss in obese men. Eur J Endocrinol 2003;148:535-542.
149. Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan. G. Adipenectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 2003; 52:1779-1785.
150. Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab 1998; 83:2907-2910.
151. Steffen DG, Arakelian MC, Phinney G, Brown LJ, Mersmann HJ. Effect of nutritional status on swine adipose tissue lipolytic activities. J Anim Sci 1981; 52:1306-1311.
152. Mersmann HJ, McNeil MD. Lipid mobilization by obese and lean pigs infused with the beta-adrenergic agonist isoproterenol. J Anim Sci 1989; 67:1992-1996.
153. McNeel RL, Ding ST, Smith EO, Mersmann HJ. Effect of feed restriction on adipose tissue transcript concentrations in genetically lean and obese pigs. J Anim Sci 2000; 78: 934-942.
154. Mersmann HJ, Koong LJ. Effect of plane of nutrition on adipose tissue lipid metabolism in genetically obese and lean pigs. J Nutr 1984; 114:862-868.
155. Gasic S, Tian B, Green A. Tumor necrosis factor-alpha stimulates lipolysis in adipocytes by decreasing Gj protein concentrations. J Biol Chem 1999; 274: 6770 -6775.
156. Zhang HH, Halbleib M, Ahmad F, Manganiello VC, Greenberg AS. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 2002; 51: 2929-2935.
157. Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M. Resistin release by human adipose tissue explants in primary culture. Biochem Biophys Res Commun 2003; 300: 674-678.