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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)3567-3579
Number of pages13
JournalJournal of Clinical Investigation
Volume126
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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Skeletal Muscle Fibers
Muscle Cells
Homeostasis
Insulin
Lipids
Insulin Resistance
Thioredoxins
Glucose
Arrestin
High Fat Diet
Transcription Factors
Obesity
Muscles
Liver
Proteins
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ahn, B., Soundarapandian, M. M., Sessions, H., Peddibhotla, S., Roth, G. P., Li, J. L., ... 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

MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling. / Ahn, Byungyong; Soundarapandian, Mangala M.; Sessions, Hampton; Peddibhotla, Satyamaheshwar; Roth, Gregory P.; Li, Jian Liang; Sugarman, Eliot; Koo, Ada; Malany, Siobhan; Wang, Miao; Yea, Kyungmoo; Brooks, Jeanne; Leone, Teresa C.; Han, Xianlin; Vega, Rick B.; Kelly, Daniel P.

In: Journal of Clinical Investigation, Vol. 126, No. 9, 01.09.2016, p. 3567-3579.

Research output: Contribution to journalArticle

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
Ahn B, Soundarapandian MM, Sessions H, Peddibhotla S, Roth GP, Li JL et al. MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling. Journal of Clinical Investigation. 2016 Sep 1;126(9):3567-3579. https://doi.org/10.1172/JCI87382
Ahn, Byungyong ; Soundarapandian, Mangala M. ; Sessions, Hampton ; Peddibhotla, Satyamaheshwar ; Roth, Gregory P. ; Li, Jian Liang ; Sugarman, Eliot ; Koo, Ada ; Malany, Siobhan ; Wang, Miao ; Yea, Kyungmoo ; Brooks, Jeanne ; Leone, Teresa C. ; Han, Xianlin ; Vega, Rick B. ; Kelly, Daniel P. / MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 9. pp. 3567-3579.
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