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 7

SBI-993 inhibits muscle and hepatic TAG accumulation and reduces MondoA target gene expression in vivo.

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SBI-993 inhibits muscle and hepatic TAG accumulation and reduces MondoA ...
Mice maintained on an HFD for 8 weeks were administered SBI-993 (50 mg/kg, q.d., s.c.) or a vehicle control for the final week of HFD feeding. Target gene expression (A) and total triglyceride content (B) were measured in skeletal muscle (gastrocnemius) and liver in mice maintained on a control diet (CD) or HFD (n = 6–10 mice per group). *P < 0.05 versus CD/vehicle; †P < 0.05 versus HFD/vehicle; 1-way ANOVA with Bonferroni’s post-hoc test. (C) Blood glucose levels are shown following a glucose tolerance test (1 g/kg glucose, i.p.) after dosing with SBI-993 or vehicle (n = 6 per group). Data represent the mean ± SEM. *P < 0.05 HFD/vehicle versus HFD/SBI-993; 2-way ANOVA with Tukey’s multiple comparisons post-hoc test. (D) Western blot analysis of gastrocnemius skeletal muscle whole-cell lysate from mice receiving an acute insulin challenge (1.5 U/kg for 10 minutes) to examine insulin signaling using p-Akt (S473). Graph shows quantification of Western blot analysis (n = 4–6 per condition). Representative Western blots are shown. *P < 0.05 versus CD/vehicle; †P < 0.05 versus HFD/vehicle; 1-way ANOVA with Bonferroni’s post-hoc test.