The heart requires a continuous supply of energy but has little capacity for energy storage and thus relies on exogenous metabolic sources. We previously demonstrated that cardiac MED13 modulates systemic energy homeostasis in mice. In the present study, we sought to define the extra-cardiac tissue(s) that respond to cardiac MED13 signaling. Cardiac over-expression of MED13 in mice (MED13cTg) confers a lean phenotype that is associated with increased lipid uptake, beta-oxidation and mitochondrial content in white adipose tissue (WAT) and liver. Cardiac expression of MED13 decreases metabolic gene expression and metabolite levels in heart and liver but enhances them in WAT. Although exhibiting increased energy expenditure in the fed state, MED13cTg mice are metabolically flexible and adapt to fasting. These findings demonstrate that MED13 acts within the heart to promote systemic energy expenditure in extra-cardiac energy depots and point to an unexplored metabolic communication system between the heart and other tissues.