Poster Presentation: Scott P. Connelly

ABSTRACT

Myocardin-related transcription factors mediate adipocyte dysfunction during obesity

Scott P. Connelly, Stephen R. Farmer, Matthew D. Layne.

Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine

Adipocytes are critical for regulating appetite, systemic inflammation, and insulin sensitivity of metabolic organs. In obese individuals, adipocytes become dysfunctional, increasing risks of type-2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. One hallmark of adipocyte dysfunction in obese individuals is the emergence of a fibroblast-like actin network and transcriptome. The drivers of this potentially pathological phenotype have not been fully explored. Additionally, how the robust actin network in obese adipocytes impairs cell function has not been described. Myocardin-related transcription factor A (MRTFA) is a mechanically regulated transcriptional cofactor which coactivates serum response factor (SRF) to regulate fibroblast activation. Our group and others have shown that mechanical activation of MRTFA impairs progenitor differentiation into adipocytes, indicating these pathways may be involved in impairing regulators of the adipocyte phenotype. These observations support the hypothesis that MRTFA re-activation in mature adipocytes regulates adipocyte disfunction. To test this hypothesis, protein lysates from the adipocytes of lean and obese mice were isolated and demonstrated an increase in MRTFA, SRF, and actin abundance in obese adipocytes. Furthermore, immunofluorescent staining of adipose tissue from lean and obese mice confirmed an increase in adipose tissue MRTFA expression and the localization of MRTFA to adipocyte nuclei, indicating its activation. To further investigate MRTFA activation in obese adipocytes, we analyzed an existing single-nuclei sequencing dataset of the adipose tissue from lean and obese mice and confirmed that transcriptional signatures of MRTFA are upregulated in obese murine adipocytes. Additionally, human sequencing data revealed that MRTFA expression correlated with pathological markers in adipocyte subpopulations. Constitutively activating MRTFA in in vitro adipocytes demonstrated that MRTFA activation produces a fibroblast-like phenotype, characterized by robust actin polymerization and morphological projections. These findings indicate that the MRTF pathway is potentially targetable to treat mechanically-driven adipose tissue dysfunction during obesity.