A MED13-dependent Skeletal Muscle Gene Program Controls Systemic Glucose Homeostasis and Hepatic Metabolism

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2016 Feb 18

PMID 26883362

Citations 24

Authors

Leonela Amoasii

William Holland

Efrain Sanchez-Ortiz

Kedryn K Baskin

Mackenzie Pearson

Shawn C Burgess

Benjamin R Nelson

Rhonda Bassel-Duby

Eric N Olson

Affiliations

Soon will be listed here.

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.

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