Characterization of the role of sphingomyelin synthase 2 in glucose metabolism in whole-body and peripheral tissues in mice

Sugimoto, Masayuki; Shimizu, Yoichi; Ukon, Naoyuki; Nishijima, Ken‐ichi; Wakabayashi, Masato; Yoshioka, Takeshi; Higashino, Kenichi; Numata, Yoshito; Okuda, Tomohiko; Tamaki, Nagara; Hanamatsu, Hisatoshi; Igarashi, Yasuyuki; Kuge, Yuji

doi:10.1016/j.bbalip.2016.04.019

Cited by 36 publications

(24 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, sphingomyelin may regulate insulin signalling through inactivation of AKT (Figure ) . In contrast, although global SMS2 knockout mice showed reduced insulin resistance induced by high‐fat diet, liver‐specific SMS2 knock out in mice had no effect on whole body insulin resistance, even though significant decreases in hepatic sphingomyelin were observed . In that study, genetic ablation of SMS2 elevated glucose clearance and this was attributed to activation of glucose uptake into insulin‐targeted tissues such as skeletal muscle.…”

Section: Experimental Evidence For the Association Between Phospholipmentioning

confidence: 91%

The relationship between phospholipids and insulin resistance: From clinical to experimental studies

Chang

Hatch

Wang

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

Insulin resistance induced by high‐fat diet and impropriate life style is a major contributor to the pathogenesis of metabolic disease. However, the underlying molecular mechanisms remain unclear. Recent studies in metabolic dysfunction have extended this beyond simply elevated cholesterol and triglycerides levels and have identified a key role for lipid metabolism. For example, altered phospholipid metabolism has now become central in the pathogenesis of metabolic disease. In this review, we discuss the association between insulin sensitivity and phospholipid metabolism and highlight the most significant discoveries generated over the last several decades. Finally, we summarize the current knowledge surrounding the molecular mechanisms related to phospholipids and insulin resistance and provide new insight for future research into their relationship.

show abstract

Section: Experimental Evidence For the Association Between Phospholipmentioning

confidence: 91%

The relationship between phospholipids and insulin resistance: From clinical to experimental studies

Chang

Hatch

Wang

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…Smpd1-4). Palmitate induced expression of Sgms2, an isoform of particular interest, as its depletion from mice was previously shown to increase insulin sensitivity (6,8,22). Under these conditions, the expression of mRNA for SMPD1, which encodes acid sphingomyelinase, decreased; by contrast, the transcripts encoding Sphingolipid profiling of C2C12 myotubes exposed to GW4869 or D609 with or without palmitate (n > 5) * and # denote significance of palmitate and D609, respectively, at p Ͻ 0.05.…”

Section: Effect Of An Sms Inhibitor On Insulin Signaling and Mitochonmentioning

confidence: 99%

“…Several groups (8,22) have found that Sgms2 deficiency prevented high fat diet-induced obesity and insulin resistance in mice. The data presented herein suggest that SM is unlikely to be a direct antagonist of insulin action in skeletal muscle.…”

Section: Tablementioning

confidence: 99%

A Role for Ceramides, but Not Sphingomyelins, as Antagonists of Insulin Signaling and Mitochondrial Metabolism in C2C12 Myotubes

Park

Kaddai

Ching

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The accumulation of sphingolipids in obesity leads to impairments in insulin sensitivity and mitochondrial metabolism, but the precise species driving these defects is unclear. We have modeled these obesity-induced effects in cultured C2C12 myotubes, using BSA-conjugated palmitate to increase synthesis of endogenous sphingolipids and to inhibit insulin signaling and oxidative phosphorylation. Palmitate (a) induced the accumulation of sphingomyelin (SM) precursors such as sphinganine, dihydroceramide, and ceramide; (b) inhibited insulin stimulation of a central modulator of anabolic metabolism, Akt/PKB; (c) inhibited insulin-stimulated glycogen synthesis; and (d) decreased oxygen consumption and ATP synthesis. Under these conditions, palmitate failed to alter levels of SMs, which are the most abundant sphingolipids, suggesting that they are not the primary intermediates accounting for the deleterious palmitate effects. Treating cells with a pharmacological inhibitor of SM synthase or using CRISPR to knock out the Sms2 gene recapitulated the palmitate effects by inducing the accumulation of SM precursors and impairing insulin signaling and mitochondrial metabolism. To profile the sphingolipids that accumulate in obesity, we performed lipidomics on quadriceps muscles from obese mice with impaired glucose tolerance. Like the cultured myotubes, these tissues accumulated ceramides but not SMs. Collectively, these data suggest that SM precursors such as ceramides, rather than SMs, are likely nutritional antagonists of metabolic function in skeletal muscle.

show abstract

“…Indeed, ceramide content is elevated in liver and adipose tissue from high-fat-fed animals, but it is controversial whether ceramides accumulate in skeletal muscle during obesity and diabetes, and whether they lead to musclespecific and whole-body insulin resistance (5). Some studies find elevated net levels of total ceramides in the skeletal muscle of diet-induced insulin-resistant mice and humans (6)(7)(8), but many report no change in muscle ceramide content in human and mouse models of obesity and type 2 diabetes (9-11), often despite significant increases in plasma and liver ceramide content (12,13). This dissociation of changes in skeletal muscle ceramide levels from changes in insulin sensitivity questions the role for muscle ceramides in mediating fat-induced insulin resistance (5).…”

mentioning

confidence: 99%

Sphingolipid changes do not underlie fatty acid-evoked GLUT4 insulin resistance nor inflammation signals in muscle cells[S]

Pillon

Frendo‐Cumbo

Jacobson

et al. 2018

Journal of Lipid Research

View full text Add to dashboard Cite

Ceramides contribute to obesity-linked insulin resistance and inflammation in vivo, but whether this is a cell-autonomous phenomenon is debated, particularly in muscle, which dictates whole-body glucose uptake. We comprehensively analyzed lipid species produced in response to fatty acids and examined the consequence to insulin resistance and pro-inflammatory pathways. L6 myotubes were incubated with BSA-adsorbed palmitate or palmitoleate in the presence of myriocin, fenretinide, or fumonisin B1. Lipid species were determined by lipidomic analysis. Insulin sensitivity was scored by Akt phosphorylation and glucose transporter 4 (GLUT4) translocation, while pro-inflammatory indices were estimated by IκBα degradation and cytokine expression. Palmitate, but not palmitoleate, had mild effects on Akt phosphorylation but significantly inhibited insulin-stimulated GLUT4 translocation and increased expression of pro-inflammatory cytokines and Ceramides, hexosylceramides, and sphingosine-1-phosphate significantly heightened by palmitate correlated negatively with insulin sensitivity and positively with pro-inflammatory indices. Inhibition of sphingolipid pathways led to marked changes in cellular lipids, but did not prevent palmitate-induced impairment of insulin-stimulated GLUT4 translocation, suggesting that palmitate-induced accumulation of deleterious lipids and insulin resistance are correlated but independent events in myotubes. We propose that muscle cell-endogenous ceramide production does not evoke insulin resistance and that deleterious effects of ceramides in vivo may arise through ancillary cell communication.

show abstract

Characterization of the role of sphingomyelin synthase 2 in glucose metabolism in whole-body and peripheral tissues in mice

Cited by 36 publications

References 65 publications

The relationship between phospholipids and insulin resistance: From clinical to experimental studies

The relationship between phospholipids and insulin resistance: From clinical to experimental studies

A Role for Ceramides, but Not Sphingomyelins, as Antagonists of Insulin Signaling and Mitochondrial Metabolism in C2C12 Myotubes

Sphingolipid changes do not underlie fatty acid-evoked GLUT4 insulin resistance nor inflammation signals in muscle cells[S]

Contact Info

Product

Resources

About