Whereas the role of adipose tissue in glucose and lipid homeostasis is widely recognized, its role in systemic protein and amino acid metabolism is less well-appreciated. In vitro and ex vivo experiments suggest that adipose tissue can metabolize substantial amounts of branched chain amino acids (BCAAs). However, the role of adipose tissue in regulating BCAA metabolism in vivo is controversial. Interest in the contribution of adipose tissue to BCAA metabolism has been renewed with recent observations demonstrating down-regulation of BCAA oxidation enzymes in adipose tissue in obese and insulin-resistant humans. Using gene set enrichment analysis, we observe alterations in adipose-tissue BCAA enzyme expression caused by adipose-selective genetic alterations in the GLUT4 glucosetransporter expression. We show that the rate of adipose tissue BCAA oxidation per mg of tissue from normal mice is higher than in skeletal muscle. In mice overexpressing GLUT4 specifically in adipose tissue, we observe coordinate down-regulation of BCAA metabolizing enzymes selectively in adipose tissue. This decreases BCAA oxidation rates in adipose tissue, but not in muscle, in association with increased circulating BCAA levels. To confirm the capacity of adipose tissue to modulate circulating BCAA levels in vivo, we demonstrate that transplantation of normal adipose tissue into mice that are globally defective in peripheral BCAA metabolism reduces circulating BCAA levels by 30% (fasting)-50% (fed state). These results demonstrate for the first time the capacity of adipose tissue to catabolize circulating BCAAs in vivo and that coordinate regulation of adiposetissue BCAA enzymes may modulate circulating BCAA levels.The branched chain amino acids (BCAAs) 2 , leucine, isoleucine, and valine, are three of the nine essential amino acids and are relatively abundant in the food supply accounting for ϳ20% of total protein intake (1). In contrast to the other 17 amino acids, which are predominantly metabolized in the liver, BCAAs are poorly metabolized during first pass through the liver as the liver expresses only low levels of the mitochondrial branched chain aminotransferase (BCAT2 or BCATm), the first enzyme in the catabolism of BCAAs in most peripheral tissues (2, 3). BCAAs are therefore in a unique position among amino acids to signal to the periphery and the brain the amino acid content of a meal. Circulating BCAAs, acting as nutrient signals, regulate protein synthesis, and degradation, and insulin secretion, and have been implicated in central nervous system control of food intake and energy balance (4 -7). Our knowledge of the physiologic mechanisms which regulate circulating BCAA levels remains incomplete. In this study, we provide evidence that adipose tissue contributes to the regulation of circulating BCAAs.Over the last two decades, adipose tissue has emerged as a key endocrine organ and a regulator of integrated fuel homeostasis. Whereas its role in glucose and lipid homeostasis is widely recognized, its role in systemic protein ...