title: A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism.
abstract: The Mediator complex governs gene expression by linking upstream signaling pathways with the basal transcriptional machinery. However, how individual Mediator subunits may function in different tissues remains to be investigated. Through skeletal muscle-specific deletion of the Mediator subunit MED13 in mice, we discovered a gene regulatory mechanism by which skeletal muscle modulates the response of the liver to a high-fat diet. Skeletal muscle-specific deletion of MED13 in mice conferred resistance to hepatic steatosis by activating a metabolic gene program that enhances muscle glucose uptake and storage as glycogen. The consequent insulin-sensitizing effect within skeletal muscle lowered systemic glucose and insulin levels independently of weight gain and adiposity and prevented hepatic lipid accumulation. MED13 suppressed the expression of genes involved in glucose uptake and metabolism in skeletal muscle by inhibiting the nuclear receptor NURR1 and the MEF2 transcription factor. These findings reveal a fundamental molecular mechanism for the governance of glucose metabolism and the control of hepatic lipid accumulation by skeletal muscle. Intriguingly, MED13 exerts opposing metabolic actions in skeletal muscle and the heart, highlighting the customized, tissue-specific functions of the Mediator complex.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Leonela
authors.initials: L
authors.lastname: Amoasii
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: William
authors.initials: W
authors.lastname: Holland
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Efrain
authors.initials: E
authors.lastname: Sanchez-Ortiz
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Kedryn K
authors.initials: KK
authors.lastname: Baskin
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Pearson
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Nelson
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000235:genetics; D017353:Gene Deletion; D019848:Gene Expression Regulation, Archaeal / Q000235:genetics; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*
chemical_list: C519602:Med13 protein, mouse; D056892:Mediator Complex; D005947:Glucose
keywords: NURR1/NR4A2; glucose homeostasis; mediator complex; skeletal muscle