Cell Metab. 19, 96–108 (2014)

Exercise is protective against obesity and type 2 diabetes. Peroxisome proliferator–activated receptor-γ coactivator 1α (PGC-1α) controls metabolic adaptation to exercise in muscle and can lead to the expression of brown adipocyte–specific genes in white adipose tissue (WAT). Roberts et al. employed a metabolomics approach to identify small molecule metabolites secreted from PGC-1α–expressing muscle that contribute to these protective phenotypes. In media from cultured mouse myoblasts overexpressing PGC-1a, b-aminoisobutyric acid (BAIBA) was enriched compared with media from normal myoblasts. In cultured human pluripotent cells differentiated into WAT, BAIBA led to increased expression of brown fat–specific genes and raised the basal rate of oxygen consumption. In mice, BAIBA led to augmented expression of brown adipocyte–specific genes and hepatic β oxidation genes—including peroxisome proliferator–activated receptor α (PPARa)—and decreased body fat and improved glucose tolerance. In cultured hepatocytes, BAIBA raised the rate of maximal oxygen consumption and expression of β oxidation genes. A small molecule inhibitor of PPARα abrogated these effects, indicating that BAIBA mediated its effects via PPARα. Taken together, these data suggest exercise-induced release of BAIBA from skeletal muscle can promote the expression of brown adipocyte–specific genes in fat and stimulate β oxidation via PPARα in the liver, and these molecular changes are at least partially responsible for the beneficial effects of exercise.