MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling

Ahn, Byoung Joon; Soundarapandian, Mangala M.; Sessions, H; Peddibhotla, Satyamaheshwar; Roth, Gregory P.; Li, Jian Liang; Sugarman, Eliot; Koo, Ada; Malany, Siobhan; Wang, Miao; Yea, Kyungmoo; Brooks, Jeanne Kaye; Leone, Teresa C.; Han, Xianlin; Vega, Rick B.; Kelly, Daniel P.

doi:10.1172/jci87382

Cited by 56 publications

(73 citation statements)

References 57 publications

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“…Our data would suggest that this antiapoptotic effect of Exendin-4 occurs through MondoA inhibition. Recently, an inhibitor of MondoA has been reported to have beneficial effects on insulin and glucose handling in high fatfed mice (39). Based on our findings of MondoA actions in b-cells, it would be interesting to explore whether its specific inhibition here could be in part responsible for the observed improved glucose handling.…”

Section: Discussionmentioning

confidence: 87%

MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

et al. 2017

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Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human β-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in β-cells that coordinates transcriptional response to elevated glucose levels.

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Section: Discussionmentioning

confidence: 87%

MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

et al. 2017

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“…Tightly regulated control of muscle metabolism is essential to performance and the well being of the whole organism (1)(2)(3). With exercise, muscle coordinately upregulates the metabolism of glucose, fatty acids, and amino acids for energy production, and this response varies with time of day (4).…”

Section: Introductionmentioning

confidence: 99%

Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogramming

Quattrocelli¹,

Zelikovich²,

Jiang³

et al. 2019

JCI Insight

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“…In response to rising blood glucose, the ATP-sensitive potassium (K ATP ) channel in β cells is inhibited, leading to membrane depolarization, elevation of cytosolic calcium, and insulin secretion (Newgard and McGarry, 1995; Nichols, 2006). Previous studies have shown that O-GlcNAc transferase (OGT) (Bond and Hanover, 2015; Erickson et al, 2013; Hardiville and Hart, 2014; Ruan et al, 2013), and ChREBP and MondoA together with their binding partner Mlx (Havula and Hietakangas, 2012; Postic et al, 2007; Uyeda and Repa, 2006) contribute to the transcriptional effects of glucose in diverse cell types, including skeletal muscle (Ahn et al, 2016; Stoltzman et al, 2008). However, whether glucose directly engages nutrient sensing pathways in skeletal myocytes to regulate glucose disposal remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Glucose Sensing by Skeletal Myocytes Couples Nutrient Signaling to Systemic Homeostasis

et al. 2017

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SUMMARY Skeletal muscle is a major site of postprandial glucose disposal. Inadequate insulin action in skeletal myocytes contributes to hyperglycemia in diabetes. While glucose is known to stimulate insulin secretion by β cells, whether it directly engages nutrient signaling pathways in skeletal muscle to maintain systemic glucose homeostasis remains largely unexplored. Here we identified the Baf60c-Deptor-AKT pathway as a target of muscle glucose sensing that augments insulin action in skeletal myocytes. Genetic activation of this pathway improved postprandial glucose disposal in mice, whereas its muscle-specific ablation impaired insulin action and led to postprandial glucose intolerance. Mechanistically, glucose triggers KATP channel-dependent calcium signaling that promotes HDAC5 phosphorylation and nuclear exclusion, leading to Baf60c induction and insulin-independent AKT activation. This pathway is engaged by the anti-diabetic drugs sulfonylureas to exert their full glucose-lowering effects. These findings uncover an unexpected mechanism of glucose sensing in skeletal myocytes that contributes to homeostasis and therapeutic action.

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MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling

Cited by 56 publications

References 57 publications

MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogramming

Glucose Sensing by Skeletal Myocytes Couples Nutrient Signaling to Systemic Homeostasis

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