MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling
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
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
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Research Article Metabolism

MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling

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.

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

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Figure 6

MondoA depletion mimics action of SBI-477 in human skeletal myotubes.

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MondoA depletion mimics action of SBI-477 in human skeletal myotubes. TX...
TXNIP and ARRDC4 gene expression was measured following treatment with 10 μM SBI-477 (A) or siRNA-mediated MondoA (MLXIP) KD (B) (n = 4). *P < 0.05 versus vehicle (A) or nontargeting siRNA control (siCon) (B). (C) 2-DG uptake following MondoA KD (or siCon) in the absence or presence of insulin (n = 5). *P < 0.05 versus siCon/vehicle; †P < 0.05 versus siCon/insulin. (D) Cellular TAG levels following MondoA KD in the absence or presence of 100 μM oleate (n = 5). *P < 0.05 versus siCon/oleate. Effect of MondoA KD (E) or SBI-477 treatment (F) on the expression of genes encoding lipogenic and triglyceride synthesis enzymes (n = 4). *P < 0.05 versus vehicle or siCon. Data represent the mean ± SD. Statistical significance in all panels was determined by Mann-Whitney U test.