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
View: Text | PDF
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

×

Figure 8

MondoA directs myocyte fuel homeostatic checkpoint functions.

Options: View larger image (or click on image) Download as PowerPoint
MondoA directs myocyte fuel homeostatic checkpoint functions. Proposed g...
Proposed gene-regulatory (red arrows) and metabolic “checkpoint” responses (blue arrows) downstream of MondoA. MondoA is a glucose “sensor” that is directly activated by glycolytic metabolites that stimulate nuclear import of MondoA. Once activated, MondoA functions as a “brake” to limit carbon entry into the cell via increasing levels of TXNIP, an inhibitor of insulin signaling and glucose uptake. In addition, MondoA promotes energy storage through activation of enzymes involved in lipid and glycogen synthesis. Thus, MondoA may serve to limit carbon intake and fuel burning during conditions of “plenty.” However, in states of chronic nutrient excess, persistent activation of MondoA may become maladaptive, contributing to a vicious cycle of cellular lipid accumulation (TAG synthesis) and insulin resistance (TXNIP-mediated suppressive effects).