The actin cytoskeleton during adipocyte formation
Torres, Lynes Judith
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In addition to providing heat insulation and mechanical cushioning, adipose tissue regulates overall metabolic homeostasis and serves as an essential energy storage site. Excess adipose tissue, or obesity, is on the rise in the US among all demographics. The expansion of adipose tissue results from both adipocyte hypertrophy and hyperplasia but the mechanisms that regulate these processes are not fully understood. Destabilizing actin has been shown to promote adipogenesis while actin stabilization inhibits this process. In addition, decreased actin synthesis is known to occur. However, these studies examined total actin and did not consider that actin is in fact a family of functionally diverse isoforms and that individual isoforms may have different functions in adipogenesis. I hypothesized that actin isoforms contribute differently to adipogenic actin reorganization. To measure this, I developed a novel fractionation method that allowed for the reliable quantification of actin polymerization. I used this actin fractionation method to identify an early loss in polymerized α-smooth muscle actin (α-SMA) relative to polymerized β-actin and γ-actin and to also rule out a role for the actin severing protein gelsolin in the loss of polymerized actin. Furthermore, I showed that the loss of α-SMA expression precedes the loss of β-actin and γ-actin expression. A known regulator of actin cytoskeleton genes is the transcription factor serum response factor (SRF) and its co-activator, myocardin related transcription factor (MRTF). I identified a role for MRTF/SRF in the downregulation of actin expression during adipogenesis, particularly α-SMA. There was an additional cAMP-responsive decrease in α-SMA expression during the initiation of adipogenesis by exposure to established inducers. Overall, my findings are consistent with growing evidence suggesting that genetic markers of smooth muscle cells, including α-SMA, help control adipogenic commitment. Understanding these early stages of adipogenesis could open new therapeutic avenues for obesity and its co-morbidities.