title: A cardiac microRNA governs systemic energy homeostasis by regulation of MED13.
abstract: 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.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Grueter
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.forename: Brett A
authors.initials: BA
authors.lastname: Johnson
authors.forename: Susan M
authors.initials: SM
authors.lastname: DeLeon
authors.forename: Lillian B
authors.initials: LB
authors.lastname: Sutherland
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qi
authors.forename: Laurent
authors.initials: L
authors.lastname: Gautron
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2; D004734:Energy Metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control
chemical_list: D035683:MicroRNAs; C543978:Mirn208 microRNA, mouse; D005947:Glucose