Downstream signaling pathways in mouse adipose tissues following acute in vivo administration of fibroblast growth factor 21.
Downstream signaling pathways in mouse adipose tissues following acute in vivo administration of fibroblast growth factor 21.
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DOI：
10.1371/journal.pone.0073011
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mehmet H
中科院分区：
文献类型：
--
作者：
Muise ES;Souza S;Chi A;Tan Y;Zhao X;Liu F;Dallas-Yang Q;Wu M;Sarr T;Zhu L;Guo H;Li Z;Li W;Hu W;Jiang G;Paweletz CP;Hendrickson RC;Thompson JR;Mu J;Berger JP;Mehmet H
FGF 21是一种新型分泌蛋白，在临床前物种中具有稳健的抗糖尿病、抗肥胖和抗动脉粥样硬化活性。在目前的研究中，我们研究了急性给予小鼠生长因子后FGF 21下游的信号转导途径。聚焦于脂肪组织，我们鉴定了FGF 21介导的下游信号传导事件和靶向接合生物标志物。具体而言，脂肪组织的RNA分析和脂肪细胞的磷酸蛋白质组分析，在FGF 21处理后，揭示了几种相关蛋白质中基因表达和翻译后修饰的几种特定变化，特别是磷酸化。从C57 BL/6（喂食常规食物或HFD）和db/db小鼠分离的白色脂肪组织的亲和微阵列分析鉴定了超过150种稳健的潜在RNA转录物和超过50种潜在的分泌蛋白，其被FGF 21急性改变超过1.5倍。磷酸化分析鉴定了3 T3-L1脂肪细胞中超过130种被FGF 21调节超过1.5倍的磷酸化蛋白。结合基因和磷蛋白分析数据的生物信息学分析确定了许多已知的代谢途径，如葡萄糖摄取、胰岛素受体信号传导、Erk/Mapk信号传导级联和脂质代谢。此外，在治疗后的转录和蛋白磷酸化水平上观察到许多与FGF 21信号传导具有迄今未知联系的新事件。我们的结论是，这种组合的“组学”方法不仅可以用于识别新的治疗方法的强大的生物标志物，但也可以提高我们对下游信号通路的理解;在这里提出的例子中，新的FGF 21介导的信号在脂肪组织中的事件已被揭示，值得进一步调查。
FGF21 is a novel secreted protein with robust anti-diabetic, anti-obesity, and anti-atherogenic activities in preclinical species. In the current study, we investigated the signal transduction pathways downstream of FGF21 following acute administration of the growth factor to mice. Focusing on adipose tissues, we identified FGF21-mediated downstream signaling events and target engagement biomarkers. Specifically, RNA profiling of adipose tissues and phosphoproteomic profiling of adipocytes, following FGF21 treatment revealed several specific changes in gene expression and post-translational modifications, specifically phosphorylation, in several relevant proteins. Affymetrix microarray analysis of white adipose tissues isolated from both C57BL/6 (fed either regular chow or HFD) and db/db mice identified over 150 robust potential RNA transcripts and over 50 potential secreted proteins that were changed greater than 1.5 fold by FGF21 acutely. Phosphoprofiling analysis identified over 130 phosphoproteins that were modulated greater than 1.5 fold by FGF21 in 3T3-L1 adipocytes. Bioinformatic analysis of the combined gene and phosphoprotein profiling data identified a number of known metabolic pathways such as glucose uptake, insulin receptor signaling, Erk/Mapk signaling cascades, and lipid metabolism. Moreover, a number of novel events with hitherto unknown links to FGF21 signaling were observed at both the transcription and protein phosphorylation levels following treatment. We conclude that such a combined "omics" approach can be used not only to identify robust biomarkers for novel therapeutics but can also enhance our understanding of downstream signaling pathways; in the example presented here, novel FGF21-mediated signaling events in adipose tissue have been revealed that warrant further investigation.
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