β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-Oxidation and Is Inversely Correlated with Cardiometabolic Risk Factors

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1 alpha transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1 alpha-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1 alpha, and identified beta-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and beta-oxidation in hepatocytes both in vitro and in vivo through a PPAR alpha-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.