PTHrP inhibits adipocyte differentiation by down-regulating PPARγ activity via a MAPK-dependent pathway
PTHrP inhibits adipocyte differentiation by down-regulating PPARγ activity via a MAPK-dependent pathway
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DOI：
10.1210/en.142.11.4900
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发表时间：
2001-11-01
期刊：
影响因子：
4.8
通讯作者：
Karaplis, AC
中科院分区：
文献类型：
--
作者：
Chan, GK;Deckelbaum, RA;Karaplis, AC
我们检查了PTHrP调节前脂肪细胞系3 T3-L1终末分化的能力。这些细胞表达内源性PTHrP及其受体，但在分化为成熟脂肪细胞后表达水平不可检测。稳定过表达PTHrP的细胞在诱导成脂时不能分化，并以更快的速度增殖。在PTHrP转染的3T3-L1细胞中MAPK活性升高，用PKA抑制剂H-8处理降低了这种活性。用PD098059抑制MAPK激酶允许PTHrP转染的3T3-L1细胞进行终末分化。虽然PPARgamma基因表达水平在PTHrP转染的细胞中保持相对恒定，但PPARgamma磷酸化增强。此外，PTHrP降低了在曲格列酮存在下PPAR γ刺激转录的能力。在PTHrP转染的细胞中，PPARr调节的脂肪细胞特异性基因aP2的表达短暂上升，然后下降。这些结果表明PTHrP可以通过PKA途径增加3T3-L1细胞中的MAPK活性，从而增强PPAR-gamma磷酸化。这种修饰可以减弱PPAR-gamma的转录增强活性，并减少脂肪细胞特异性基因的表达。因此，这些研究表明，PTHrP可能会抑制前脂肪细胞的终末分化，并描述了一个分子途径，通过它可以实现这一行动。
We examined the capacity of PTHrP to modulate the terminal differentiation of the preadipocytic cell line, 3T3-L1. These cells express endogenous PTHrP and its receptor, but expression levels were undetectable after differentiation into mature adipocytes. Cells stably overexpressing PTHrP failed to differentiate when induced to undergo adipogenesis and proliferated at a faster rate. MAPK activity was elevated in PTHrP-transfected 3T3-L1 cells, and treatment with the PKA inhibitor H-8 decreased this activity. Inhibition of MAPK kinase with PD098059 permitted terminal differentiation of PTHrP-transfected 3T3-L1 cells to proceed. Although PPAR gamma gene expression levels remained relatively constant in the PTHrP-transfected cells, PPAR gamma phosphorylation was enhanced. Furthermore, the capacity of PPAR gamma to stimulate transcription in the presence of troglitazone was diminished by PTHrP. Expression of the PPARr-regulated adipocyte-specific gene aP2 transiently rose and then fell in PTHrP-transfected cells. These results indicate that PTHrP can increase MAPK activity in 3T3-L1 cells via the PKA pathway, thereby enhancing PPAR-gamma phosphorylation. This modification can inactivate the transcriptional enhancing activity of PPAR-gamma and diminish the expression of adipocyte-specific genes. These studies therefore demonstrate that PTHrP may inhibit the terminal differentiation of preadipocytes and describe a molecular pathway by which this action can be achieved.