PROJECT SUMMARY Obesity is an accelerating worldwide health crisis associated with the comorbidities of metabolic syndrome. An alluring possibility to combat obesity and metabolic disease is to activate beige adipocytes, brown-like adipocytes that reside in white adipose tissue with the capacity to conduct non-shivering adaptive thermogenesis (NSAT). To this end, mice engineered to have increased beige fat activity resist weight gain, have enhanced insulin sensitivity, and improved lipid levels. Further, a recent study of the FTO obesity risk allele in humans implicated impaired beige fat activity as a causal factor associated with human obesity. Thus, increasing beige fat activity appears to be a novel and viable method to treat metabolic disease. However, doing so will likely require a greatly improved understanding of the mechanisms governing the development and function of beige adipocytes. It is well appreciated that thyroid hormone and its receptors, the thyroid hormone receptors (TRs), are associated with thermogenesis, although the basis for this action is not clear. Recently, we demonstrated that pharmacological TR activation by a synthetic agonist, GC-1, can profoundly induce beige fat activation, `beiging', in vitro and in vivo. This finding has led us to believe that TR signaling represents a crucially important, yet overlooked, component of beige fat activation. Thus, the overarching theme of this proposal is to precisely define the role of TR signaling in beige fat function, specifically to test our hypotheses that TR activation is both necessary and sufficient to induce beige fat activation. We seek to do so within the following 3 aims: 1) To determine whether TR activation is sufficient to induce white adipocyte beiging. 2) To determine whether TR signaling is necessary for WAT beiging and required for beiging by agents such as β-AR agonists and cold exposure. 3) To determine the origin of beige adipocytes that arise following TR activation. At the completion of these aims we expect to understand how TR signaling regulates beige fatdevelopment and activity, knowledge which we expect will help us develop new anti-obesity therapies.