TGFbeta-mediated Transcriptional Reprogramming of Mature Adipocytes in Obesity

脂肪组织在肥胖的情况下变得功能失调，并且显著地促进胰岛素抵抗和代谢综合征的其他特征的发展。其中很大一部分被认为是由炎症和纤维化引起的。虽然纤维化已在其他组织中得到广泛研究，但脂肪组织纤维化仍未被探索。我们已经产生了初步的数据，即高脂肪喂养改变了成熟脂肪细胞的转录和表观基因组状态，减少了脂肪形成基因的表达，促进了通常与肌成纤维细胞相关的纤维形成环境的形成。此外，我们的数据表明转录因子Smad 3和SRF在这个过程中的作用。在本申请中，我们将使用鼠和人细胞培养模型以及小鼠体内研究的组合来询问TGFβ在脂肪纤维化中的作用，重点关注两个下游转录效应子的相对贡献：传统的Smad 2/3/4途径通常与TGFβ−介导的信号传导相关，以及SRF。我们将重点关注导致PPARγ作用降低的事件以及促进纤维化的事件，评估这些不同结果相互影响的程度。我们的目标是去卷积复杂的转录事件，促进脂肪纤维化，并建立这些途径是否易于处理， 治疗干预

Adipose tissue becomes dysfunctional in the setting of obesity, and contributes significantly to the development of insulin resistance and other features of metabolic syndrome. A large part of this is believed to result from inflammation and fibrosis. Although fibrosis has been extensively studied in other tissues, adipose tissue fibrosis is still unexplored. We have generated preliminary data that that high fat feeding alters the transcriptional and epigenomic state of mature adipocytes, reducing adipogenic gene expression and promoting the elaboration of a fibrogenic milieu usually associated with myofibroblasts. Furthermore, our data suggest a role for the transcription factors Smad3 and SRF in this process. In this application, we will use a combination of murine and human cell culture models as well as in vivo studies in mice to interrogate the role of TGFβ in adipose fibrosis, focusing on the relative contributions of two downstream transcriptional effectors: the traditional Smad2/3/4 pathway typically associated with TGFβ−mediated signaling, as well as SRF. We will focus on events that lead to reduced PPARγ action and also events that promote fibrosis, assessing how much these different outcomes influence one another. Our objective is to deconvolute the complex transcriptional events that promote adipose fibrosis and to establish whether these pathways are tractable to therapeutic intervention.