Peroxisome proliferator-activated receptor gene expression in human tissues - Effects of obesity, weight loss, and regulation by insulin and glucocorticoids
Peroxisome proliferator-activated receptor gene expression in human tissues - Effects of obesity, weight loss, and regulation by insulin and glucocorticoids
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DOI：
10.1172/jci119424
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发表时间：
1997-05-15
影响因子：
15.9
通讯作者：
Flier, JS
中科院分区：
文献类型：
--
作者：
VidalPuig, AJ;Considine, RV;Flier, JS
过氧化物酶体增殖物激活受体(PPAR-γ)在脂肪形成和脂肪细胞基因表达中起关键作用，是胰岛素增敏药物噻唑烷二酮的受体。人PPARγ基因在体内的组织表达和调控潜力尚不清楚，我们已经克隆了人PPARγ基因的部分cDNA，并建立了一种RNase保护实验，可以同时测量PPAR Gamma 1和PPAR Gamma 2剪接变异体。在脂肪组织中均有大量表达，PPARγ1在肝脏和心脏中低水平表达，而在骨骼肌中均有低水平表达。为了验证肥胖与脂肪组织中PPAR-γ的异常表达有关的假设，我们对14名瘦身受试者和24名肥胖者皮下脂肪组织中的PPAR-Gamma基因剪接变体进行了定量。肥胖女性PPARγ2/18s的脂肪表达增加(14.25attomol PPAR Gamma 2/18s，P=0.003)，男性和女性PPARγ2/18s的表达均显著增加，而PPAR Gamma 1/18s的表达无明显差异，且呈显著正相关(r=0.70，P<；0.001)在PPARγ2/Gamma 1比值与体重指数之间，我们还观察到女性皮下脂肪组织中PPAR Gamma 1和PPAR Gamma 2 mRNA性二型性表达均高于男性。为了确定减肥对PPAR Gamma mRNA表达的影响，另外7名肥胖者被给予低卡路里饮食(800KCAL)，直到体重减轻10%。脂肪PPAR-Gamma 2mRNA的平均表达下降了25%(体重下降10%后，P=0.0250)，但在体重维持4周后恢复到治疗前的水平，没有看到PPAR-1的营养调节。体外实验显示，胰岛素和皮质类固醇对体外培养的人脂肪细胞诱导PPAR-γ的表达具有协同作用。我们得出的结论是：(A)人PPAR-Gamma基因在骨骼肌中有表达，这种表达在一定程度上不太可能是由于脂肪污染。(B)肥胖者脂肪组织来源的RNA增加了PPAR-Gamma-2mRNA的表达，并增加了PPAR-Gamma-2/Gamma-1剪接变异体的比例，与BMI成正比；(C)低热量饮食特异性地下调了肥胖者脂肪组织中PPAR-Gamma 2mRNA的表达；(D)胰岛素和皮质类固醇在体外作用于分离的人脂肪细胞后，协同诱导PPAR-Gamma mRNA的表达；(E)体内对PPAR-Gamma-2mRNA水平的调节是控制脂肪细胞发育和功能的额外调节水平，并可能为肥胖时脂肪细胞数量和功能的改变提供分子机制。
The peroxisome proliferator activated receptor (PPAR gamma) plays a key role in adipogenesis and adipocyte gene expression and is the receptor for the thiazolidinedione class of insulin-sensitizing drugs. The tissue expression and potential for regulation of human PPAR gamma gene expression in vivo are unknown, We have cloned a partial human PPAR gamma cDNA, and established an RNase protection assay that permits simultaneous measurements of both PPAR gamma 1 and PPAR gamma 2 splice variants. Both gamma 1 and gamma 2 mRNAs were abundantly expressed in adipose tissue, PPAR gamma 1 was detected at lower levels in liver and heart, whereas both gamma 1 and gamma 2 mRNAs were expressed at low levels in skeletal muscle. To examine the hypothesis that obesity is associated with abnormal adipose tissue expression of PPAR gamma, we quantitated PPAR gamma mRNA splice variants in subcutaneous adipose tissue of 14 lean and 24 obese subjects. Adipose expression of PPAR gamma 2 mRNA was increased in human obesity (14.25 attomol PPAR gamma 2/18S in obese females vs 9.9 in lean, P = 0.003), This increase was observed in both male and females, In contrast, no differences were observed in PPAR gamma 1/18S mRNA expression, There was a strong positive correlation (r = 0.70, P < 0.001) between the ratio of PPAR gamma 2/gamma 1 and the body mass index of these patients, We also observed sexually dimorphic expression with increased expression of both PPAR gamma 1 and PPAR gamma 2 mRNAs in the subcutaneous adipose tissue of women compared with men. To determine the effect of weight loss on PPAR gamma mRNA expression, seven additional obese subjects were fed a low calorie diet (800 Kcal) until 10% weight loss was achieved. Mean expression of adipose PPAR gamma 2 mRNA fell 25% (P = 0.0250 after a 10% reduction in body weight), but then increased to pretreatment levels after 4 wk of weight maintenance, Nutritional regulation of PPAR gamma 1 was not seen, In vitro experiments revealed a synergistic effect of insulin and corticosteroids to induce PPAR gamma expression in isolated human adipocytes in culture, We conclude that: (a) human PPAR gamma mRNA expression of both splice variants is seen in skeletal muscle; to an extent that is unlikely to be due to adipose contamination. (b) RNA derived from adipose tissue of obese humans has increased expression of PPAR gamma 2 mRNA, as well as an increased ratio of PPAR gamma 2/gamma 1 splice variants that is proportional to the BMI; (c) a low calorie diet specifically down-regulates the expression of PPAR gamma 2 mRNA in adipose tissue of obese humans; (d) insulin and corticosteroids synergistically induce PPAR gamma mRNA after in vitro exposure to isolated human adipocytes; and (e) the in vivo modulation of PPAR gamma 2 mRNA levels is an additional level of regulation for the control of adipocyte development and function, and could provide a molecular mechanism for alterations in adipocyte number and function in obesity.