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

Abstract

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.See also: M Nakamura & J Sadoshima (December 2014)

A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism

“…We showed previously that cardiac MED13 overexpression impacts systemic metabolism and enhances lipid oxidation and mitochondrial activity in WAT, BAT, and the liver (Grueter et al 2012;Baskin et al 2014). The findings of the present study reveal an antithetical function of MED13 in skeletal muscle, in which it suppresses glucose metabolism under conditions of HFD-induced insulin resistance.…”

“…Additional components of the Mediator complex are involved in fatty acid, cholesterol, and lipid homeostasis (Yang et al 2006;Zhao et al 2012;Tsai et al 2013;Chu et al 2014). We reported that cardiac overexpression of MED13 increases energy consumption and confers a lean phenotype in mice (Grueter et al 2012;Baskin et al 2014). However, the functions of MED13 in other tissues have not been explored.…”

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

“…This submodule regulates gene expression through its dynamic association with the Mediator core complex and through its Cdk8 activity (19)(20)(21). We recently reported the novel observation that cardiac Med13 functions to regulate whole-body energy homeostasis (22,23) and that Med1 is essential in postnatal and adult cardiomyocytes (24); however, the function of Mediator kinase activity has yet to be determined. Knockdown and overexpression studies in other systems have shown that Cdk8 can impart both activating and repressive effects on transcription in celland gene-specific contexts (25)(26)(27)(28).…”

MED12 regulates a transcriptional network of calcium-handling genes in the heart

“…The kinase submodule, containing MED12, MED13, CDK8, and Cyclin C (12), can repress transcription through allosteric inhibition of RNA Pol II binding to the core submodule (13) but can also activate transcription by promoting Pol II recruitment to target genes via specific transcription factors (14). We previously demonstrated that cardiac MED13 regulates systemic energy homeostasis through signaling to extracardiac tissues (15,16), but the roles of the other kinase components in the heart have not been investigated.…”

“…The kinase submodule, containing MED12, MED13, CDK8, and Cyclin C (12), can repress transcription through allosteric inhibition of RNA Pol II binding to the core submodule (13) but can also activate transcription by promoting Pol II recruitment to target genes via specific transcription factors (14). We previously demonstrated that cardiac MED13 regulates systemic energy homeostasis through signaling to extracardiac tissues (15,16), but the roles of the other kinase components in the heart have not been investigated.MED12, a component of the Mediator kinase submodule, is encoded on the X chromosome, and missense mutations are associated with a variety of X-linked disorders (17)(18)(19). Developmental signaling pathways and transcription factors converge on MED12, which acts as a transcriptional hub required to coordinate development (20)(21)(22)(23).…”