P300 or CBP is required for insulin-stimulated glucose uptake in skeletal muscle and adipocytes.

Vitor F Martins,Ji E Park,Omer Keinan,Andrew Philp,Christina Ha,Robert R Henry,Theodore P Ciaraldi,Carrie E Mccurdy,Alexandra Stanley,Kristoffer Svensson,Joseph E Aslan,Byron Hetrick,Chao-Wei Hung,Samuel A Labarge,Larry L David,Alan R Saltiel,Dion Banoian,Simon Schenk,Gretchen A Meyer

doi:10.1172/jci.insight.141344

Abstract

While current thinking posits that insulin signaling to glucose transporter 4 (GLUT4) exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle caused a complete loss of insulin-stimulated glucose uptake. Similarly, brief (i.e., 1 hour) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulated this phenotype in human and rodent myotubes, 3T3-L1 adipocytes, and mouse muscle. Mechanistically, these effects were due to p300/CBP-mediated regulation of GLUT4 exocytic translocation and occurred downstream of Akt signaling. Taken together, we highlight a fundamental role for acetylation and p300/CBP in the direct regulation of insulin-stimulated glucose transport in skeletal muscle and adipocytes.

Highlights

Current thinking posits that phosphorylation-based signaling regulates insulin stimulation to glucose transporter 4 (GLUT4) exocytic translocation and glucose uptake, in both skeletal muscle and adipose tissue (1, 2)
Here we report that loss of both p300 and CBP acetyltransferase activity causes a complete loss of insulin-stimulated glucose uptake in skeletal muscle and adipocytes and does so via inhibition of insulin-stimulated GLUT4 exocytic translocation
Particular kinases have been established as fundamental to insulin action; for example, PI3K and Akt2 are required for insulin-stimulated glucose uptake independent of muscle fiber type, tissue type, or sex (1, 2)

Summary

Introduction

Current thinking posits that phosphorylation-based signaling regulates insulin stimulation to glucose transporter 4 (GLUT4) exocytic translocation and glucose uptake, in both skeletal muscle and adipose tissue (1, 2). Recent acetylomics studies have revealed that many proteins key to both insulin signaling and GLUT4 exocytic translocation can be reversibly acetylated on lysine residues (3–5). Lysine acetylation is known to regulate biological processes through transcription via acetylation of histones and transcription factors (6). Reversible lysine acetylation requires the enzymatic addition or removal of acetyl groups on lysine residues by acetyltransferases or deacetylases, respectively (6). While the deacetylases have been studied extensively for both their transcriptional (7–9) and non-transcriptional (10, 11) control of insulin action, the contribution of the acetyltransferases remains poorly understood

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