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

doi:10.1172/JCI87382

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

Department of New Biology

Sanford Burnham Prebys Medical Discovery Institute

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

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.

Original language	English
Pages (from-to)	3567-3579
Number of pages	13
Journal	Journal of Clinical Investigation
Volume	126
Issue number	9
DOIs	https://doi.org/10.1172/JCI87382
State	Published - 1 Sep 2016

Bibliographical note

Funding Information:
We dedicate this manuscript to the memory of Gregory Roth. We thank Donald Ayer, Timothy Osborne, and Peter Phelan for helpful discussions; Lorenzo Thomas for assistance with manuscript preparation; David Terry for measurements of SBI-993 compound exposure; Julio Ayala and the Cardiometabolic Phenotyping Core for assistance with the glucose tolerance tests; Feng Qi, Subramaniam Shyamalagovindarajan, and the Bioinformatics and Genomics Cores at SBP-LN for assistance with microarray studies; Ling Lai, Orlando Rodriguez, and Caron Stonebrook for assistance with the animal studies; and William Esler and Jeff Pfefferkorn (Pfizer Inc.) for assistance with discussion and measurements of DGAT1/2 and MGAT1/2/3 activity. This work was supported by NIH grants R01 DK045416, R24 DK092781, and R24 DK084969 (to DPK)

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10.1172/JCI87382

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Ahn, B., Soundarapandian, M. M., Sessions, H., Peddibhotla, S., Roth, G. P., Li, J. L., Sugarman, E., Koo, A., Malany, S., Wang, M., Yea, K., Brooks, J., Leone, T. C., Han, X., Vega, R. B., & Kelly, D. P. (2016). MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling. Journal of Clinical Investigation, 126(9), 3567-3579. https://doi.org/10.1172/JCI87382

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title = "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.",

author = "Byungyong Ahn and Soundarapandian, {Mangala M.} and Hampton Sessions and Satyamaheshwar Peddibhotla and Roth, {Gregory P.} and Li, {Jian Liang} and Eliot Sugarman and Ada Koo and Siobhan Malany and Miao Wang and Kyungmoo Yea and Jeanne Brooks and Leone, {Teresa C.} and Xianlin Han and Vega, {Rick B.} and Kelly, {Daniel P.}",

note = "Funding Information: We dedicate this manuscript to the memory of Gregory Roth. We thank Donald Ayer, Timothy Osborne, and Peter Phelan for helpful discussions; Lorenzo Thomas for assistance with manuscript preparation; David Terry for measurements of SBI-993 compound exposure; Julio Ayala and the Cardiometabolic Phenotyping Core for assistance with the glucose tolerance tests; Feng Qi, Subramaniam Shyamalagovindarajan, and the Bioinformatics and Genomics Cores at SBP-LN for assistance with microarray studies; Ling Lai, Orlando Rodriguez, and Caron Stonebrook for assistance with the animal studies; and William Esler and Jeff Pfefferkorn (Pfizer Inc.) for assistance with discussion and measurements of DGAT1/2 and MGAT1/2/3 activity. This work was supported by NIH grants R01 DK045416, R24 DK092781, and R24 DK084969 (to DPK)",

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Ahn, B, Soundarapandian, MM, Sessions, H, Peddibhotla, S, Roth, GP, Li, JL, Sugarman, E, Koo, A, Malany, S, Wang, M, Yea, K, Brooks, J, Leone, TC, Han, X, Vega, RB & Kelly, DP 2016, 'MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling', Journal of Clinical Investigation, vol. 126, no. 9, pp. 3567-3579. https://doi.org/10.1172/JCI87382

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T1 - MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling

AU - Ahn, Byungyong

AU - Soundarapandian, Mangala M.

AU - Sessions, Hampton

AU - Peddibhotla, Satyamaheshwar

AU - Roth, Gregory P.

AU - Li, Jian Liang

AU - Sugarman, Eliot

AU - Koo, Ada

AU - Malany, Siobhan

AU - Wang, Miao

AU - Yea, Kyungmoo

AU - Brooks, Jeanne

AU - Leone, Teresa C.

AU - Han, Xianlin

AU - Vega, Rick B.

AU - Kelly, Daniel P.

N1 - Funding Information: We dedicate this manuscript to the memory of Gregory Roth. We thank Donald Ayer, Timothy Osborne, and Peter Phelan for helpful discussions; Lorenzo Thomas for assistance with manuscript preparation; David Terry for measurements of SBI-993 compound exposure; Julio Ayala and the Cardiometabolic Phenotyping Core for assistance with the glucose tolerance tests; Feng Qi, Subramaniam Shyamalagovindarajan, and the Bioinformatics and Genomics Cores at SBP-LN for assistance with microarray studies; Ling Lai, Orlando Rodriguez, and Caron Stonebrook for assistance with the animal studies; and William Esler and Jeff Pfefferkorn (Pfizer Inc.) for assistance with discussion and measurements of DGAT1/2 and MGAT1/2/3 activity. This work was supported by NIH grants R01 DK045416, R24 DK092781, and R24 DK084969 (to DPK)

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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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DO - 10.1172/JCI87382

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SN - 0021-9738

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SP - 3567

EP - 3579

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

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ER -

MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling

Abstract

Bibliographical note

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