Aberrant cardiac metabolism is associated with obesity, type 2 diabetes and heart failure. The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function, however little is known about the role of the heart as a metabolic organ. Nuclear hormone receptors, such as thyroid hormone receptor play an important role in cardiovascular disease by significantly altering expression of genes involved in maintaining metabolic activity. The Mediator, a large multiprotein complex functions as a hub to control gene expression through association with transcriptional activators and repressors. We tested the hypothesis that Med13, a component of the Mediator complex, regulates cardiac function in a gain-of-function mouse model. Trangsenic mice overexpressing Med13 in the heart are lean, have increased energy expenditure, are resistant to high fat diet-induced obesity and have enhanced cardiac contractility. Microarray analysis and biochemical assays show that in vivo and in vitro Med13 selectively inhibits nuclear hormone receptor target genes of energy metabolism. These results implicate the Mediator complex regulates energy balance and cardiac contractility and suggests that the heart may function as a key component of mammalian energy homeostasis.
In vitro assessment of human nuclear hormone receptor activity and cytotoxicity of the flame retardant mixture FM 550 and its triarylphosphate and brominated components
