Healthy Remodeling of Obese Adipose Tissue

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Obesity has reached pandemic proportions contributing to the dramatic increases in several metabolic diseases, for which there is no effective therapy. Adipose (AT) is a dynamic tissue capable of dramatically changing its overall morphology (remodeling) in response to a host of effectors. These dynamic events can remodel the tissue to be both beneficial as well as harmful. Obese AT undergoes extensive remodeling, which includes fibrosis. In humans, fibrosis is a hallmark of obesity that is tightly associated with inflammation. Remodeling of AT can also be beneficial and coincide with conditions that enhance insulin sensitivity and reduce inflammation. A variety of pharmacological and natural agents can induce extensive remodeling of AT, which include recruitment of brown-like adipocytes (beige) to white adipose tissues (WAT). This browning process is considered to be beneficial because it contributes to an increase in energy expenditure resulting in decreased ectopic fat deposition and enhanced insulin sensitivity. Recent studies suggest that browning is compromised in chronically obese and fibrotic WAT. For browning to be a strategy to treat obesity-associated disorders, we need to be able to induce it in obese individuals. A strategy is to target pathways that inhibit fibrosis while enhancing beige adipocyte formation during obesity. We recently reported that myocardin related transcription factor A (MRTFA), regulates conversion of vascular progenitors to beige adipocytes. In fact, we reported that mice with a global deletion of MRTFA have extensive WAT browning and are resistant to short-term diet-induced obesity (DIO) and its associated insulin resistance. MRTFA is also a known regulator of myofibroblast (ECM producing cells) activation and fibrosis in other tissues including liver and heart. Since MRTFA appears to regulate the fate of vascular progenitors to beige adipocytes and myofibroblasts, it is very possible that beige adipocyte expansion is directly compromised in AT fibrosis. We suggest, therefore, that effectors that suppress MRTFA activity in AT are potential targets for development of obesity therapeutics. Our overall hypothesis proposes that deletion of MRTFA in vascular progenitors will limit fibrosis and sensitize obese AT to browning effectors. We propose four aims to test this hypothesis: 1. Determine the fate of WT and MRTFA–/– WAT vascular progenitors in response to diet and browning. 2. Does pharmacological inhibition of MRTFA regulate the fate of mural cells and enhance WAT browning? 3. Identify the mechanisms by which MRTFA regulates the fate of AT mural cells. 4. Does deletion of MRTFA exclusively in mural progenitors enhance browning of WAT and protect mice from diet-induced fibrosis during obesity? The successful completion of these aims will provide novel insights into pathways that regulate beige AT formation, thus advancing our understanding of how to therapeutically target adipose tissues for the treatment of human obesity.