Title: “Regulation of adipose lineage plasticity in obesity” Project Summary/Abstract A potential therapeutic target to curb the global obesity and diabetes epidemic is thermogenic beige fat within white adipose tissue. Unlike white adipocyte which stores fat, beige adipocyte absorbs sugar and fat from the blood and then burns it. Recent studies indicate that beige adipocytes are present in adult human, and their activities are correlated with a metabolically healthy phenotype. Due to its promise to reduce adiposity and improve insulin sensitivity, various molecular cues to induce beige adipocyte lineage have been extensively investigated. However, most of these studies focus on young and healthy adult. Relatively little work has been done investigating the white and beige adipocyte plasticity and their regulation in obese and old subjects, who constitutes a large percentage of the obesity-diabetes epidemic. Our long-term goal is to understand adipose lineage development and their plasticity in health and disease. During the K01 award period, we identified a perivascular smooth muscle actin (Sma) positive adipocyte progenitor cells (APCs) that is capable of generating both white and beige adipocytes. Mechanistically, we identified a platelet-derived growth factor receptor α (Pdgfrα) as a novel regulator of white and beige adipocyte switch, the deletion of which leads to beige lineage maintenance in high fat diet induced obesity. We observed that mutant mice with the perdurance of beige adipocytes were resistant to weight gain, improved glucose metabolism, and had better overall energy expenditure. We hypothesize that this would be a novel approach to utilize white-to-beige fat switch as a therapy for diet-induced and age-associated obesity. We will test the hypothesis that modulating APC Pdgfrα activity will alter adipose lineage plasticity in obesity with the following 2 aims: 1: Determine the APC-intrinsic role of Pdgfrα in diet-induced obesity; and 2: Determine the mechanisms by which Pdgfrα controls beiging potential in obese and old mice. In this proposal, we plan to leverage our innovative experimental models to understand how Pdgfrα controls the fate of white and beige APCs, and how this increased beige life span regulates adiposity and metabolism in obese and old animals. It is hoped that the results of this proposal will shed light on novel molecular targets and cellular processes that can be therapeutically exploited to improve energy expenditure for the prevention and treatment of obesity and its associated metabolic disorders, including diabetes. This R03 application's proposed aims are based on strong preliminary data generated from the ongoing K01, will allow developing the rationale and provide additional preliminary data for an R01 application in this area.