MED13‐dependent signaling from the heart confers leanness by enhancing metabolism in adipose tissue and liver

The heart requires a continuous supply of energy but has little capacity for energy storage and thus relies on exogenous metabolic sources. We previously showed that cardiac MED13 modulates systemic energy homeostasis in mice. Here, we sought to define the extra‐cardiac tissue(s) that respond to cardiac MED13 signaling. We show that cardiac overexpression of MED13 in transgenic (MED13cTg) mice 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 in the heart but enhances them in WAT. Although exhibiting increased energy expenditure in the fed state, MED13cTg mice metabolically adapt to fasting. Furthermore, MED13cTg hearts oxidize fuel that is readily available, rendering them more efficient in the fed state. Parabiosis experiments in which circulations of wild‐type and MED13cTg mice are joined, reveal that circulating factor(s) in MED13cTg mice promote enhanced metabolism and leanness. 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. Synopsis Cardiac MED13 enhances the use by the heart and the body of fuel resources available after or between meals. The heart thereby regulates systemic energy expenditure via circulating factors to promote enhanced metabolism and leanness. Cardiac overexpression of MED13 increases lipid metabolism in adipose tissue and liver. Enhanced metabolism in MED13cTg mice is not pathological, as MED13cTg mice metabolically adapt to fasting. Leanness is regulated by circulating factors in MED13cTg mice. Metabolic rates of wild‐type mice are increased by systemic delivery of “lean factors”. Graphical Abstract Cardiac MED13 enhances the use by the heart and the body of fuel resources available after or between meals. The heart thereby regulates systemic energy expenditure via circulating factors to promote enhanced metabolism and leanness.