Vasculature and Beige Remodeling of Obese Adipose Tissue

About This Grant

Adipose tissue (AT) remodeling plays a key role in metabolic homeostasis and healthy expansion of AT is required to preserve insulin sensitivity. Pathological consequences of dysfunctional AT remodeling include chronic inflammation and fibrosis that contribute to the adverse outcomes of obesity. Beiging (cold-induced recruitment of thermogenic adipocytes in white adipose tissue (WAT) is potentially a healthy means to remodel AT because the newly formed beige adipocytes not only enhance energy expenditure, but they also counteract unhealthy remodeling. For beiging to be a strategy to treat obesity, we need to induce it in obese individuals. Studies show however that beiging declines with obesity and aging. We propose a strategy that inhibits pathways contributing to the unhealthy remodeling of WAT while enhancing beige adipocyte recruitment. We propose that obesity prevents beiging because the pool of beige progenitors is redirected to other fates. In a recent study, we discovered a previously unrecognized population of quiescent mural cells expressing transgelin (SM22) that can rapidly transition into adipocyte progenitors (APCs) in response to cold exposure. We hypothesize that beige progenitors arise from mural cells of the microvasculature during angiogenesis; a process that is significantly attenuated in obese WAT. Serum response factor (SRF) and its associated coactivator, myocardin-related transcription factor A (MRTFA) are regulators of mesenchymal stem cell (MSC) fate decisions and angiogenesis. We and others discovered that inhibition of MRTFA activity promotes conversion of progenitors to beige adipocytes. Furthermore, MRTFA-/– mice are protected from diet-induced obesity and insulin resistance, which leads us to hypothesize that these effects are mediated (at least in part) by a beneficial AT remodeling including beige adipocyte recruitment, enhanced angiogenesis and inhibition of fibrosis. We hypothesize that MRTFA/SRF signaling opposes conversion of vascular mural cells into beige adipocytes while promoting macrophage-driven fibrogenesis. Thus, we predict that mice lacking MRTFA activity in mural cells and macrophages will exhibit enhanced beige remodeling and remain responsive to browning agents even during obesity. Small molecules that attenuate MRTFA activity in combination with agents that mimic cold are, therefore, potential therapeutics for obesity-related disorders. We propose three aims: 1: Deconstruct the beige-associated remodeling of WAT in MRTFA-deficient mice. 2: Establish a role for MRTFA in regulating recruitment of beige progenitors from mural cells in WAT. 3: Define the mechanisms by which MRTFA regulates the conversion of mural cells to beige progenitors. Impact: At the completion of these aims, we will have defined novel mechanisms facilitating beige remodeling during obesity and identified targets for development of anti-obesity therapeutics.