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 3

SBI-477 stimulates glucose uptake and activates insulin signaling in the absence of insulin.

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SBI-477 stimulates glucose uptake and activates insulin signaling in the...
Human skeletal myotubes were incubated with SBI-477 at the indicated concentration for 24 hours and then treated with or without insulin (100 nM) for 30 minutes. Glucose (2-DG) uptake (A) and glycogen synthesis rates (B) were measured (n = 5) as described in Methods. (A and B) *P < 0.05 versus vehicle, no insulin; †P < 0.05 versus vehicle with insulin; 2-way ANOVA with Tukey’s post-hoc test. (C) Western blot analysis of human myotubes treated with SBI-477 for 24 hours was performed to determine the effect on steps of the insulin-signaling pathway using specific Akt and IRS-1 phosphorylation sites as endpoints. Insulin treatment (100 nM) for 30 minutes was used as a positive control. (D) Graph shows quantitation of the Western blot data in C (n = 5). *P < 0.05 and **P < 0.01 versus vehicle; 1-way ANOVA with Bonferroni’s post-hoc test. Data represent the mean ± SD. Ins, insulin; Veh, vehicle.