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目的:脂肪组织是一个内分泌器官已逐渐得到了肯定,它能分泌多种信号分子如:脂联素和抵抗素.过氧化物酶体增殖物激活受体(peroxisome proliferator activated receptor γ ,PPARγ)在脂肪组织高水平表达,胰岛素增敏剂-噻唑烷二酮类药物是它的选择性激动剂,噻唑烷二酮类药物如罗格列酮的胰岛素增敏作用部分是通过激活PPARγ调节脂联素(胰岛素增敏分子)和抵抗素(涉及胰岛素抵抗)表达介导的.但现在不同研究发现PPARγ激动剂对抵抗素的表达调控方向存在矛盾,我们的问题是当抵抗素表达增加的情况下脂联素的表达还能否上调.方法:用3T3-L1细胞株作为研究模型,分别用溶媒对照、罗格列酮(10 μmol/L)、GW9662(5 μmol/L)或罗格列酮+GW9662作用细胞,然后检测脂联素和抵抗素mRNA表达变化情况.结果:与对照组相比,罗格列酮分别增加脂联素和抵抗素mRNA水平 1.77 和 1.66 倍,其差异具有统计学意义(P＜0.05);重要的是GW9662也增加脂联素水平(1.57 倍, P＜0.05)但对抵抗素无影响.罗格列酮和GW9662两者合用时,仍上调adiponectin mRNA水平(对照组的 1.87 倍, P＜0.05),抵抗素的增加与罗格列酮单用比弱下降(对照组的 1.31 倍, P＜0.05).结论:本研究为PPARγ激动剂(罗格列酮)和拮抗剂(GW9662)都上调脂联素的转录提供了新的证据,两者合用时GW9662不阻断罗格列酮诱导的脂联素上调作用. 综合这些数据提示噻唑烷二酮类药上调脂联素的机制可能不依赖于PPARγ.并且, GW9662在增加脂联素水平的同时不上调抵抗素水平的特性进一步支持PPARγ拮抗剂用于临床治疗胰岛素抵抗的可能性.降低抵抗素表达可能不是罗格列酮胰岛素增敏作用的重要机制.我们的结果为将来研究噻唑烷二酮类药物对人脂肪细胞因子表达在剂量和时间上提供了一定的基础.“,”BACKGROUND: There is a growing recognition that the adipose tissue is an endocrine organ that secretes signaling molecules such as adiponectin and resistin. The peroxisome proliferator activated receptor γ (PPARγ) is expressed in high levels in the adipose tissue. Thiazolidinediones are selective PPARγ agonists with insulin-sensitizing properties. It has been postulated that thiazolidinediones such as rosiglitazone exert their pharmacodynamic effects in part through modulation of resistin (implicated in insulin resistance) and adiponectin (an insulin-sensitizing molecule) expression subsequent to activation of PPARγ. There are conflicting data, however, on the biological direction in which resistin expression is modulated by PPARγ agonists and whether an increase in adiponectin expression can occur in the face of an upregulation of resistin. METHODS: Using the murine 3T3-L1 adipocytes as a model, we evaluated the changes in resistin and adiponectin gene expression after vehicle, rosiglitazone (10 μmol/L, a PPARγ agonist), GW9662 (5 μmol/L, a selective PPARγ antagonist) or GW662 and rosiglitazone co-treatment.RESULTS: In comparison to vehicle treatment, rosiglitazone increased the average adiponectin and resistin mRNA expression by 1.66- and 1.55-fold, respectively (P＜0.05). Importantly, GW9662 also upregulated adiponectin expression (by 1.57-fold, P＜0.05) but did not influence resistin expression (P＞0.05). Co-treatment with rosiglitazone and GW9662 maintained the adiponectin upregulation (1.87-fold increase from vehicle, P＜0.05) while attenuating resistin upregulation (1.31-fold increase from vehicle, P＜0.05) induced by rosiglitazone alone (1.55-fold increase from vehicle, P＜0.05). CONCLUSION: This study presents new evidence that adiponectin transcript is upregulated with both a PPARγ agonist (rosiglitazone) and antagonist (GW9662), while GW9662 co-treatment does not block rosiglitazone-induced adiponectin upregulation. These data collectively suggest that biological mechanisms independent from PPARγ may underlie thiazolidinedione pharmacodynamics on adiponectin expression. Moreover, increased adiponectin expression by GW9662, in the absence of an upregulation of resistin expression, lends further support on the emerging clinical potential of PPARγ antagonists in treatment of insulin resistance. Decreased resistin expression may not be crucial for the insulin-sensitizing effect of rosiglitazone. These findings may serve as a foundation for future dose-ranging and time-course studies of thiazolidinedione pharmacodynamics on adipocytokine expression in human adipocytes.