A Cardiac MicroRNA Governs Systemic Energy Homeostasis by Regulation of MED13

Obesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders. [Display omitted] [Display omitted] ▸ Pharmacologic inhibition of miR-208a confers resistance to diet-induced obesity ▸ Cardiac expression of MED13 enhances whole-body metabolism ▸ MED13 and miR-208a counterregulate a metabolic gene program in the heart ▸ The heart can regulate global metabolic homeostasis miR-208a regulates cardiac levels of a subunit of the Mediator complex, controlling transcription by nuclear hormone receptors. Disruption of this regulation alters whole-body energy homeostasis, revealing a role for the heart in systemic metabolic control.