Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species

Montgomery, Magdalene K; Brown, Simon H. J.; Lim, Xin Ying; Fiveash, Corrine E; Osborne, Brenna; Bentley, Nicholas; Braude, Jeremy Phillip; Mitchell, Todd W.; Coster, Adelle C.F.; Don, Anthony S.; Cooney, Gregory J.; Schmitz‐Peiffer, Carsten; Turner, Nigel

doi:10.1016/j.bbalip.2016.08.016

Cited by 71 publications

(76 citation statements)

References 49 publications

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“…Although these trends were not statistically significant, the divergent response between short and long fatty acid chain ceramides agrees with recent reports that short and long chain ceramides differently affect insulin responsiveness [26, 29, 30]. Recently, Koch et al [26] reported that vitamin D therapy specifically increased content of Cer-18:0 in circulation, which supports our finding that calcitriol alters ceramide content in subspecies-dependent manner.…”

Section: Discussionsupporting

confidence: 92%

“…It is possible that, unlike other ceramide subspecies, Cer-24:1 may enhance myocellular insulin sensitivity. Indeed, it has previously been demonstrated that very long chain length ceramides (> 22C) are associated with improved insulin sensitivity and glucose homeostasis in liver cells [29, 30]. A similar mechanism may regulate insulin sensitivity in skeletal muscle cells.…”

Section: Discussionmentioning

confidence: 99%

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Calcitriol concomitantly enhances insulin sensitivity and alters myocellular lipid partitioning in high fat-treated skeletal muscle cells

et al. 2017

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Vitamin D reduces myocellular insulin resistance, but the effects of vitamin D on intramyocellular lipid (IMCL) partitioning are unknown. The purpose of this study was to understand how calcitriol, the active vitamin D metabolite, affects insulin sensitivity and lipid partitioning in skeletal muscle cells. C2C12 myotubes were treated with calcitriol (100 nM) or vehicle control for 96 h. Insulin-stimulated Akt phosphorylation (Thr 308) was determined by western blot. Intramyocellular triacylglycerol (IMTG), diacylglycerol (DAG), and ceramide content were measured by LC/MS. IMTG partitioning and lipid droplet accumulation were assessed by oil red O. Expression of genes involved in lipid droplet packaging and lipolysis were measured by RT-PCR. Compared to vehicle-treated myotubes, calcitriol augmented insulin-stimulated pAkt. Calcitriol increased total ceramides and DAG in a subspecies-specific manner. Specifically, calcitriol preferentially increased ceramide 24:1 (1.78 fold) and di-18:0 DAG (46.89 fold). Calcitriol increased total IMTG area as assessed by oil red O, but decreased the proportion of lipid within myotubes. Calcitriol increased mRNA content of genes involved in lipid droplet packaging (perilipin 2; PLIN 2, 2.07 fold) and lipolysis (comparative gene identification-58; CGI-58 and adipose triglyceride lipase; ATGL, ~ 1.80 fold). Calcitriol alters myocellular lipid partitioning and lipid droplet packaging which may favor lipid turnover and partially explain improvements in insulin sensitivity.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Calcitriol concomitantly enhances insulin sensitivity and alters myocellular lipid partitioning in high fat-treated skeletal muscle cells

et al. 2017

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“…Our results are in agreement with various studies already carried out in animal [30] and human models, which have shown that the plasmatic levels of ceramides are correlated with aerobic capacity [31], cardio-respiratory capacity [26], diabetes, and pre-diabetes[16, 22], showing a relationship with glycidic and lipid profiles.…”

Section: Discussionsupporting

confidence: 93%

Alterations in postmenopausal plasmatic lipidome

et al. 2018

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BackgroundMenopause consists of a physiological process in women between 40 and 50 years of age, and it has substantial consequences for health, ranging from disturbances in lipid and glycidic metabolism to psychological stress and sleep alterations, thereby increasing women’s risk of cardiovascular diseases. Here, we attempted to identify potential lipid alterations not identified by the classic methods.Methods and resultsWe analyzed the serum lipid profile in 40 women in pre- and post-menopause using a lipidomic approach and mass spectrometry. Lipid species presented increased concentrations, with a difference of more than 25% post-menopause and with the ceramides (N.C23:0.Cer, N.C23:0(OH).Cer and N.C24:0(OH).Cer) standing out with a fold change of 1.68, 1.59, and 1.58, respectively. It was also observed that 14 metabolites presented a significant difference in the average concentrations between pre- and post-menopause, especially the ceramide species. Strong and positive correlations were identified between various metabolites and fasting glucose, glycated hemoglobin, total cholesterol, LDL, and triglycerides. Of note were the association ceramide (N.C10:0.Cer) and lysophosphatidylethanolamine (LPE.a.C18:0) between fasting glucose and glycated hemoglobin.ConclusionThis study detected lipid alterations, especially in ceramides, post-menopause, as well as correlations with glycidic and lipid markers, which may in the future be useful to investigate diseases associated with menopause.

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“…In contrast, hepatic ceramide content was unrelated to hepatic insulin resistance in two of the three available human studies [31,35,37]. Here, a caveat is the paucity of data on specific ceramide species (e.g., C16:0) hypothesized to mediate hepatic insulin resistance, though high-fat feeding has been reported not to increase C16:0 ceramides in five strains of mice [73]. …”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

Petersen

Shulman

2017

Trends in Pharmacological Sciences

294

240

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Although ample evidence links hepatic lipid accumulation with hepatic insulin resistance, the mechanistic basis of this association is incompletely understood and controversial. Diacylglycerols and ceramides have emerged as the two best-studied putative mediators of lipid-induced hepatic insulin resistance. Both lipids were first associated with insulin resistance in skeletal muscle, and subsequently hypothesized to mediate insulin resistance in liver. However, the putative roles for diacylglycerols and ceramides in hepatic insulin resistance have proved more complex than originally imagined, with various genetic and pharmacologic manipulations yielding a vast and occasionally contradictory trove of data to sort through. In this review, we examine the state of this field, turning a critical eye toward both diacylglycerols and ceramides as putative mediators of lipid-induced hepatic insulin resistance.

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Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species

Cited by 71 publications

References 49 publications

Calcitriol concomitantly enhances insulin sensitivity and alters myocellular lipid partitioning in high fat-treated skeletal muscle cells

Calcitriol concomitantly enhances insulin sensitivity and alters myocellular lipid partitioning in high fat-treated skeletal muscle cells

Alterations in postmenopausal plasmatic lipidome

Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

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