Downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes

Huang, Shujuan; Huang, Suling; Wang, Xi; Zhang, Qingli; Liu, Jia; Liu, Ying

doi:10.7150/ijbs.17149

Cited by 21 publications

(15 citation statements)

References 39 publications

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“…A restoration of insulin-stimulated Akt phosphorylation, despite an increase in DAG concentrations, was observed [70]. The dominance of ceramide influence versus DAG in muscle cells was confirmed in a recent study showing that lipin-1 silencing impaired insulin sensitivity in C2C12 myotubes [82]. Interestingly, the authors observed decreased intracellular DAG levels and increased ceramide accumulation in these cells [82].…”

Section: Ceramide Vs Dag As Modulators Of Muscle Insulin Sensitivitymentioning

confidence: 80%

Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

Bandet

Tan

Bourron

et al. 2019

IJMS

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Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Skeletal muscles are quantitatively the biggest glucose users in response to insulin and are considered as main targets in development of insulin-resistance. It is now clear that circulating fatty acids (FA), which are highly increased in T2D, play a major role in the development of muscle insulin-resistance. In healthy individuals, excess FA are stored as lipid droplets in adipocytes. In situations like obesity and T2D, FA from lipolysis and food are in excess and eventually accumulate in peripheral tissues. High plasma concentrations of FA are generally associated with increased risk of developing diabetes. Indeed, ectopic fat accumulation is associated with insulin-resistance; this is called lipotoxicity. However, FA themselves are not involved in insulin-resistance, but rather some of their metabolic derivatives, such as ceramides. Ceramides, which are synthetized de novo from saturated FA like palmitate, have been demonstrated to play a critical role in the deterioration of insulin sensitivity in muscle cells. This review describes the latest progress involving ceramides as major players in the development of muscle insulin-resistance through the targeting of selective actors of the insulin signaling pathway.

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Section: Ceramide Vs Dag As Modulators Of Muscle Insulin Sensitivitymentioning

confidence: 80%

Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

Bandet

Tan

Bourron

et al. 2019

IJMS

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“…They found that insulin sensitivity in such individuals is inversely correlated to the ceramide species C18:0, C20:0, C24:1 and to the total plasma ceramide level. The accumulation of ceramides produced from palmitate (through the de novo pathway) has been found to induce an inhibition of insulin signalling ( in vitro ) and diabetes ( in vivo ) . Chavez and Summers in 2012 also emphasized the role of ceramides in insulin resistance and presented a new hypothesis that implicated ceramides as a key agent in the development of insulin resistance.…”

Section: Ceramides and Insulin Resistancementioning

confidence: 99%

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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“…The lower expression of PEMT we found in VAT and the lower accumulation of lipid droplets in PEMT-deficient adipocytes are also in agreement with the findings of several groups that reported a (somewhat counterintuitive) lower adipocyte size in VAT ( 32 , 33 ) and its association with insulin resistance ( 34 ). Further studies demonstrate that PEMT expression is regulated by insulin ( 35 , 36 ), and that ceramides induce insulin resistance ( 37–39 ). Taken together with these studies, our network-based analysis and our stem cell model suggest that PEMT forms a major metabolic junction that bridges a few biosynthetic pathways into a functional pathway in adipose tissues.…”

Section: Discussionmentioning

confidence: 99%

Distinct infrastructure of lipid networks in visceral and subcutaneous adipose tissues in overweight humans

Zacharia

Saidemberg

Mannully

et al. 2020

The American Journal of Clinical Nutrition

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Background Adipose tissue plays important roles in health and disease. Given the unique association of visceral adipose tissue with obesity-related metabolic diseases, the distribution of lipids between the major fat depots located in subcutaneous and visceral regions may shed new light on adipose tissue–specific roles in systemic metabolic perturbations. Objective We sought to characterize the lipid networks and unveil differences in the metabolic infrastructure of the 2 adipose tissues that may have functional and nutritional implications. Methods Paired visceral and subcutaneous adipose tissue samples were obtained from 17 overweight patients undergoing elective abdominal surgery. Ultra-performance LC-MS was used to measure 18,640 adipose-derived features; 520 were putatively identified. A stem cell model for adipogenesis was used to study the functional implications of the differences found. Results Our analyses resulted in detailed lipid metabolic maps of the 2 major adipose tissues. They point to a higher accumulation of phosphatidylcholines, triacylglycerols, and diacylglycerols, although lower ceramide concentrations, in subcutaneous tissue. The degree of unsaturation was lower in visceral adipose tissue (VAT) phospholipids, indicating lower unsaturated fatty acid incorporation into adipose tissue. The differential abundance of phosphatidylcholines we found can be attributed at least partially to higher expression of phosphatidylethanolamine methyl transferase (PEMT). PEMT-deficient embryonic stem cells showed a dramatic decrease in adipogenesis, and the resulting adipocytes exhibited lower accumulation of lipid droplets, in line with the lower concentrations of glycerolipids in VAT. Ceramides may inhibit the expression of PEMT by increased insulin resistance, thus potentially suggesting a functional pathway that integrates ceramide, PEMT, and glycerolipid biosynthetic pathways. Conclusions Our work unveils differential infrastructure of the lipid networks in visceral and subcutaneous adipose tissues and suggests an integrative pathway, with a discriminative flux between adipose tissues.

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Downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes

Cited by 21 publications

References 39 publications

Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

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

Distinct infrastructure of lipid networks in visceral and subcutaneous adipose tissues in overweight humans

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