The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCζ

Chen, Tzu-Chieh; Benjamin, D. M.; Kuo, Taiyi; Lee, Rebecca A.; Li, Meilan; Mar, Darryl J.; Costello, Damian E.; Nomura, Daniel K.; Wang, Jen-Chywan

doi:10.1126/scisignal.aai7905

Cited by 36 publications

(33 citation statements)

References 56 publications

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“…Intriguingly, ceramides were found to play a role in insulin resistance induced by saturated fatty acids . It has also been shown that ceramides can impair glucose metabolism by acting on Akt signalling pathways through PP2A and/or PKCζ mediators . Chen et al .…”

Section: Ceramides and Insulin Resistancementioning

confidence: 99%

“…Chen et al . showed that ceramides impair glucose metabolism and induce insulin resistance through PP2A‐ and PKCζ‐dependent mechanisms . Mahfouz et al .…”

Section: Ceramides and Insulin Resistancementioning

confidence: 99%

“…Intriguingly, ceramides were found to play a role in insulin resistance induced by saturated fatty acids [58]. It has also been shown that ceramides can impair glucose metabolism by acting on Akt signalling pathways through PP2A and/or PKCf mediators [59]. Chen et al [59] showed that ceramides impair glucose metabolism and induce insulin resistance through PP2A-and PKCf-dependent mechanisms [59].…”

Section: Ceramides and Glucose Metabolismmentioning

confidence: 99%

“…It has also been shown that ceramides can impair glucose metabolism by acting on Akt signalling pathways through PP2A and/or PKCf mediators [59]. Chen et al [59] showed that ceramides impair glucose metabolism and induce insulin resistance through PP2A-and PKCf-dependent mechanisms [59]. Mahfouz et al [60] also found that ceramides induce insulin resistance through a PP2A-dependent pathway in skeletal muscles of animals.…”

Section: Ceramides and Glucose Metabolismmentioning

confidence: 99%

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Ceramides and diabetes mellitus: an update on the potential molecular relationships

Yaribeygi

Ruscica

et al. 2019

Diabet. Med.

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Recent evidence suggests that ceramides can play an important pathophysiological role in the development of diabetes. Ceramides are primarily recognized as lipid bilayer building blocks, but recent work has shown that these endogenous molecules are important intracellular signalling mediators and may exert some diabetogenic effects via molecular pathways involved in insulin resistance, β‐cell apoptosis and inflammation. In the present review, we consider the available evidence on the possible roles of ceramides in diabetes mellitus and introduce eight different molecular mechanisms mediating the diabetogenic action of ceramides, categorized into those predominantly related to insulin resistance vs those mainly implicated in β‐cell dysfunction. Specifically, the mechanistic evidence involves β‐cell apoptosis, pancreatic inflammation, mitochondrial stress, endoplasmic reticulum stress, adipokine release, insulin receptor substrate 1 phosphorylation, oxidative stress and insulin synthesis. Collectively, the evidence suggests that therapeutic agents aimed at reducing ceramide synthesis and lowering circulating levels may be beneficial in the prevention and/or treatment of diabetes and its related complications.

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Section: Ceramides and Insulin Resistancementioning

confidence: 99%

“…Chen et al . showed that ceramides impair glucose metabolism and induce insulin resistance through PP2A‐ and PKCζ‐dependent mechanisms . Mahfouz et al .…”

Section: Ceramides and Insulin Resistancementioning

confidence: 99%

Section: Ceramides and Glucose Metabolismmentioning

confidence: 99%

Section: Ceramides and Glucose Metabolismmentioning

confidence: 99%

See 2 more Smart Citations

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Yaribeygi

Ruscica

et al. 2019

Diabet. Med.

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“…These two inhibitory mechanisms are independent, targeting distinct protein domains. They appear to have cell type-dependent functional dominance (Bourbon et al 2002, Stratford et al 2004, Fox et al 2007, but operate concurrently in at least some instances (Dey et al 2007, Chen et al 2017. Despite the direct link to insulin action, however, the fact that these mechanisms have been identified primarily in muscle has prompted some researchers to raise doubts as to their relevance in other tissues (Petersen & Shulman 2017).…”

Section: Ceramides and Sphingolipidsmentioning

confidence: 99%

Defining lipid mediators of insulin resistance: controversies and challenges

Metcalfe

Smith

Turner

2019

Journal of Molecular Endocrinology

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Essential elements of all cells, lipids play important roles in energy production, signalling and as structural components. Despite these critical functions, excessive availability and intracellular accumulation of lipid is now recognised as a major factor contributing to many human diseases, including obesity and diabetes. In the context of these metabolic disorders, ectopic deposition of lipid has been proposed to have deleterious effects of insulin action. While this relationship has been recognised for some time now, there is currently no unifying mechanism to explain how lipids precipitate the development of insulin resistance. This review summarises the evidence linking specific lipid molecules to the induction of insulin resistance, describing some of the current controversies and challenges for future studies in this field.

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Transcriptional Regulatory Mechanisms in Adipose and Muscle Tissue Associated with Composite Glucometabolic Phenotypes

Langefeld

Comeau

Sharma

et al. 2018

Obesity

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ObjectiveTissue-specific gene expression is associated with individual metabolic measures. However, these measures may not reflect the true but latent underlying biological phenotype. This study reports gene expression associations with multi-dimensional gluco-metabolic characterizations of obesity, glucose homeostasis, and lipid traits.MethodsFactor analysis was computed using orthogonal rotation to construct composite phenotypes (CPs) from 23 traits in 256 non-diabetic African Americans. Genome-wide transcript expression data from adipose and muscle were tested for association with CPs, and expression quantitative trait loci (eQTL) were identified by association between cis-SNPs and gene expression.ResultsThe factor analysis identified six CPs. The CPs 1 through 6 individually explained 34%, 12%, 9%, 8%, 6% and 5% of the variation in 23 gluco-metabolic traits studied. There were 3994 and 929 CP–associated transcripts identified in adipose and muscle, respectively; CP2 had the largest number of associated transcripts. Pathway analysis identified multiple canonical pathways from the CP-associated transcripts. In adipose and muscle, significant cis-eQTL were identified for 558 and 164 CP-associated transcripts (q-value <0.01), respectively.ConclusionsAdipose and muscle transcripts comprehensively define pathways involved in regulating gluco-metabolic disorders. Cis-eQTLs for CP-associated eGenes may act as primary causal determinants of gluco-metabolic phenotypes by regulating transcription of key genes.

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The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCζ

Cited by 36 publications

References 56 publications

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Defining lipid mediators of insulin resistance: controversies and challenges

Transcriptional Regulatory Mechanisms in Adipose and Muscle Tissue Associated with Composite Glucometabolic Phenotypes

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