MondoA Coordinately Regulates Skeletal Myocyte Lipid Homeostasis and Insulin Signaling

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2016 Aug 9

PMID 27500491

Citations 38

Authors

Byungyong Ahn

Mangala M Soundarapandian

Hampton Sessions

Satyamaheshwar Peddibhotla

Gregory P Roth

Jian-Liang Li

Eliot Sugarman

Ada Koo

Siobhan Malany

Miao Wang

Kyungmoo Yea

Jeanne Brooks

Teresa C Leone

Xianlin Han

Rick B Vega

Daniel P Kelly

Affiliations

Soon will be listed here.

Abstract

Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity.

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