TGFbeta-mediated Transcriptional Reprogramming of Mature Adipocytes in Obesity

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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.