Crosstalk among energy metabolism organs mediated by MED13. Overexpression of cardiac MED13 in mice increases liver and WAT fatty acid metabolism and reduces lipid accumulation in these tissues via regulation of circulating factors. Genetic deletion of KLF5 in the mouse heart induces lower MED13 expression and higher FGF21 expression in the plasma and heart, which activates the PPARγ pathway in WAT and induces obesity. Expression of hepatic MED13 and mitochondrial fatty acid metabolism are higher in miR-378/378* knockout mice than in wild-type controls. However, opposite effects are observed upon overexpression of muscle-specific MED13 in mice and Drosophila. Upregulation of muscle MED13 in Drosophila activates the Wnt/β-catenin pathway in the muscle and adipose tissues. Wingless (Wg) acts downstream of muscle MED13 in Drosophila to enhance lipid metabolism and suppress obesity. In mice, genetic deletion of muscle MED13 improves glucose tolerance and metabolism, and confers resistance to hepatic steatosis. Moreover, skeletal muscle MED13 represses the NURR1/MEF2 cooperative pathway, thereby reducing the expression of the glucose-handling gene GLUT4 (WAT, white adipose tissue).