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

Leonela Amoasii, William Holland, Efrain Sanchez-Ortiz, Kedryn K. Baskin, Mackenzie Pearson, Shawn C. Burgess, Benjamin R. Nelson, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)434-446
Number of pages13
JournalGenes and Development
Volume30
Issue number4
DOIs
StatePublished - Feb 15 2016

Fingerprint

Skeletal Muscle
Homeostasis
Glucose
Liver
Genes
Mediator Complex
MEF2 Transcription Factors
Insulin
Lipids
Gene Expression
Adiposity
High Fat Diet
Regulator Genes
Cytoplasmic and Nuclear Receptors
Glycogen
Weight Gain
Muscles

Keywords

  • Glucose homeostasis
  • Mediator complex
  • NURR1/NR4A2
  • Skeletal muscle

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism. / Amoasii, Leonela; Holland, William; Sanchez-Ortiz, Efrain; Baskin, Kedryn K.; Pearson, Mackenzie; Burgess, Shawn C.; Nelson, Benjamin R.; Bassel-Duby, Rhonda; Olson, Eric N.

In: Genes and Development, Vol. 30, No. 4, 15.02.2016, p. 434-446.

Research output: Contribution to journalArticle

Amoasii, Leonela ; Holland, William ; Sanchez-Ortiz, Efrain ; Baskin, Kedryn K. ; Pearson, Mackenzie ; Burgess, Shawn C. ; Nelson, Benjamin R. ; Bassel-Duby, Rhonda ; Olson, Eric N. / A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism. In: Genes and Development. 2016 ; Vol. 30, No. 4. pp. 434-446.
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