MondoA drives muscle lipid accumulation and insulin resistance
Byungyong Ahn, … , Kyoung Jae Won, Daniel P. Kelly
Byungyong Ahn, … , Kyoung Jae Won, Daniel P. Kelly
Published August 8, 2019; First published July 9, 2019
Citation Information: JCI Insight. 2019;4(15):e129119. https://doi.org/10.1172/jci.insight.129119.
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Categories: Research Article Metabolism Muscle biology

MondoA drives muscle lipid accumulation and insulin resistance

Abstract

Obesity-related insulin resistance is associated with intramyocellular lipid accumulation in skeletal muscle. We hypothesized that contrary to current dogma, this linkage is related to an upstream mechanism that coordinately regulates both processes. We demonstrate that the muscle-enriched transcription factor MondoA is glucose/fructose responsive in human skeletal myotubes and directs the transcription of genes in cellular metabolic pathways involved in diversion of energy substrate from a catabolic fate into nutrient storage pathways, including fatty acid desaturation and elongation, triacylglyceride (TAG) biosynthesis, glycogen storage, and hexosamine biosynthesis. MondoA also reduces myocyte glucose uptake by suppressing insulin signaling. Mice with muscle-specific MondoA deficiency were partially protected from insulin resistance and muscle TAG accumulation in the context of diet-induced obesity. These results identify MondoA as a nutrient-regulated transcription factor that under normal physiological conditions serves a dynamic checkpoint function to prevent excess energy substrate flux into muscle catabolic pathways when myocyte nutrient balance is positive. However, in conditions of chronic caloric excess, this mechanism becomes persistently activated, leading to progressive myocyte lipid storage and insulin resistance.

Authors

Byungyong Ahn, Shibiao Wan, Natasha Jaiswal, Rick B. Vega, Donald E. Ayer, Paul M. Titchenell, Xianlin Han, Kyoung Jae Won, Daniel P. Kelly

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Figure 1

Nutrient (glucose) levels regulate MondoA activity in human skeletal myotubes.

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Nutrient (glucose) levels regulate MondoA activity in human skeletal myo...
(A) (Top) Gene expression of TXNIP was measured by quantitative reverse transcription PCR (RT-PCR) in human skeletal myotubes following deprivation of glucose for the indicated times (n = 4). (Bottom) Western blot analysis demonstrating the effect of glucose deprivation. *P < 0.05 vs. 0 hours. (B) (Top) Gene expression of TXNIP was measured by quantitative RT-PCR in human myotubes following a 6-hour glucose removal and glucose refeeding at the indicated times (n = 4). (Bottom) Western blot analysis confirmed the effect of glucose refeeding. *P < 0.05 vs. starvation 6 hours. (C) (Top) Gene expression of TXNIP was measured by quantitative RT-PCR in human myotubes following deprivation and refeeding of glucose in the absence or presence of siRNA-mediated MondoA knockdown (n = 4). (Bottom) Western blot analysis confirmed the effect of glucose in the absence or presence of MondoA KD. *P < 0.05 vs. siControl. #P < 0.05. †P < 0.05. (D) MondoA occupation on the ChoRE promoters of the TXNIP and ARRDC4 genes was measured by MondoA ChIP quantitative PCR (n = 4). *P < 0.05 vs. con. †P < 0.05 vs. starvation. (E) (Top) Gene expression of TXNIP was measured by quantitative RT-PCR in human myotubes following a 6-hour glucose removal and refeeding of 100 μM palmitate (Pal), 100 μM stearate (Ste), 100 μM oleate (Ole), and 100 μM linoleate (Lin) for 24 hours (n = 4). (Bottom) Western blot analysis of MondoA confirmed the effect of glucose refeeding. *P < 0.05 vs. veh/no starvation. (F) (Top) Gene expression of TXNIP was measured by quantitative RT-PCR in human skeletal myotubes following a 6-hour glucose removal and refeeding of 10 mM BHB, 4 mM BCAA, 25 mM glucose (Glu), and 25 mM fructose (Fru) for 24 hours (n = 4). (Bottom) Western blot analysis of TXNIP demonstrating the effect of BHB, BCAA, glucose, and fructose. *P < 0.05 vs. veh/no starvation. †P < 0.05 vs. Veh/Starvation. The data represent mean ± SD. All statistical significance determined by 1-way ANOVA with Tukey’s multiple-comparisons post hoc test.