Enhancing Energy Expending Adipocytes in White Adipose Tissue

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DESCRIPTION (provided by applicant): Obesity has reached pandemic proportions contributing to the dramatic increases in the incidence of type 2- diabetes and cardiovascular disease. The expansion of adipose tissue in obese individuals is a direct cause of these diseases due to an excessive accumulation of triglycerides (TGs) within white adipose (WAT) adipocytes. There are two major types of adipose, white that stores TGs and brown (BAT) that oxidizes them to produce heat. Until recently, it was thought that BAT only existed within the interscapular regions of newborns, but several recent investigations have identified BAT depots in the cervical, supraclavicular, axillary and paravertebral regions of adult humans. The contribution of BAT to resting metabolic rate and healthy body weight homeostasis in animals is now well established. BAT is a flexible tissue that can be recruited by stimuli and atrophies in the absence of a stimulus. In fact, studies have implicated the recruitment of brown adipocytes to WAT to explain changes in energy balance in response to different effectors. We have recently shown that lack of MRTF-A (the transcriptional coactivator of serum response factor, SRF), in mice leads to recruitment of brown-like (beige) adipocytes to WAT. In a series of in vitro studies, we have demonstrated that two members of the TGF¿ superfamily, TGF¿ and BMP7 have opposing effects on MRTF-A activity and the ability of these effectors to commit mesenchymal stem cells to an brown/beige adipogenic versus vascular lineage. Specifically, BMP7 induces brown adipogenesis by suppressing Rho kinase (ROCK) activity leading to depolymerization of F-actin and accumulation of cytoplasmic G-actin. This attenuates expression of SRF target genes by preventing translocation of MRTF- A into the nucleus. Inhibition of SRF activity with a small molecule inhibitor, CCG1423 promotes commitment of MSCs to the adipocyte lineage independent of BMP7. TGF¿ on the other hand activates SRF activity by promoting MRTF-A movement into the nucleus, which leads to suppression of adipocyte genes and activation of vascular genes including smooth muscle (SM) actin, SM heavy chain myosin (SM- MHC) and SM22. Based on these exciting data, we hypothesize that the browning of WAT is regulated by recruitment of progenitors through mechanisms involving suppression of SRF target gene expression. We propose three aims to test this hypothesis. In Aim 1, we will identify the mechanisms regulating the opposing effects of BMP7 and TGF¿ on ROCK activity and the morphology of mesenchymal stem cells. In Aim 2, we will identify the mechanisms by which MRTF-A/SRF regulates the fate of progenitors to an adipogenic versus vascular lineage. In Aim 3, we will determine the effect of MRTF-A deficiency on browning of white adipose tissue and energy balance in mice. Understanding the molecular mechanisms by which physiological effectors regulate the "browning" of WAT and identifying compounds that promote this process will significantly contribute to the development of therapeutics for obesity-associated disorders.