Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Sphingolipids and phospholipids in insulin resistance and related metabolic disorders

Key Points

  • Hypercaloric diets lead to the dysregulation of multiple lipid metabolic pathways, which contributes to the onset and progression of metabolic disease

  • Lipidomic studies are starting to decipher the dysregulation of lipid metabolism associated with metabolic disease

  • Lipid metabolic pathways represent potential therapeutic targets to prevent or delay the onset and progression of metabolic disease

  • Further animal studies and clinical trials are required to define the stage of disease at which modulation of lipid metabolism will have maximal efficacy

  • Whether intervention into a single metabolic pathway or multiple pathways will produce optimal results remains to be determined

Abstract

Obesity, insulin resistance, type 2 diabetes mellitus and cardiovascular disease form a metabolic disease continuum that has seen a dramatic increase in prevalence in developed and developing countries over the past two decades. Dyslipidaemia resulting from hypercaloric diets is a major contributor to the pathogenesis of metabolic disease, and lipid-lowering therapies are the main therapeutic option for this group of disorders. However, the fact that dysfunctional lipid metabolism extends far beyond cholesterol and triglycerides is becoming increasingly clear. Lipidomic studies and mouse models are helping to explain the complex interactions between diet, lipid metabolism and metabolic disease. These studies are not only improving our understanding of this complex biology, but are also identifying potential therapeutic avenues to combat this growing epidemic. This Review examines what is currently known about phospholipid and sphingolipid metabolism in the setting of obesity and how metabolic pathways are being modulated for therapeutic effect.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Partial biosynthetic pathway of glycerolipids and glycerophospholipids.
Figure 2: Structure of alkylglycerols and plasmalogen.
Figure 3: Biosynthetic pathway of plasmalogens.
Figure 4: Partial sphingolipid biosynthetic pathway.
Figure 5: Feedback loops between lipid metabolism and insulin resistance.

Similar content being viewed by others

References

  1. Danaei, G. et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378, 31–40 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. International Diabetes Federation. IDF Diabetes Atlas 6th edn (International Diabetes Federation, 2013).

  3. Ridker, P. M., Mora, S., Rose, L. & Jupiter Trial Study Group. Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur. Heart J. 37, 1373–1379 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Hegele, R. A. et al. Nonstatin low-density lipoprotein-lowering therapy and cardiovascular risk reduction-statement from ATVB council. Arterioscler. Thromb. Vasc. Biol. 35, 2269–2280 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Naci, H., Brugts, J. & Ades, T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials. Circ. Cardiovasc. Qual. Outcomes 6, 390–399 (2013).

    Article  PubMed  Google Scholar 

  6. Navarese, E. P. et al. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am. J. Cardiol. 111, 1123–1130 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Dobbins, R. L. et al. The composition of dietary fat directly influences glucose-stimulated insulin secretion in rats. Diabetes 51, 1825–1833 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Stein, D. T. et al. The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation. J. Clin. Invest. 100, 398–403 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Brown, M. S. & Goldstein, J. L. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 7, 95–96 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Hyötyläinen, T. & Orešicˇ, M. Optimizing the lipidomics workflow for clinical studies — practical considerations. Anal. Bioanal. Chem. 407, 4973–4993 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Wang, C., Wang, M. & Han, X. Applications of mass spectrometry for cellular lipid analysis. Mol. Biosyst. 11, 698–713 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Zhao, Y. Y., Wu, S. P., Liu, S., Zhang, Y. & Lin, R. C. Ultra-performance liquid chromatography-mass spectrometry as a sensitive and powerful technology in lipidomic applications. Chem. Biol. Interact. 220, 181–192 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Meikle, P. J., Wong, G., Barlow, C. K. & Kingwell, B. A. Lipidomics: potential role in risk prediction and therapeutic monitoring for diabetes and cardiovascular disease. Pharmacol. Ther. 143, 12–23 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Pietiläinen, K. H. et al. Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects — a monozygotic twin study. PLoS ONE 2, e218 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Weir, J. M. et al. Plasma lipid profiling in a large population-based cohort. J. Lipid Res. 54, 2898–2908 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Meikle, P. J. et al. Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PLoS ONE 8, e74341 (2013). This study represents the most detailed lipidomic analysis of plasma lipids associated with diabetes mellitus.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Meikle, P. J. et al. Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia. J. Lipid Res. 56, 2381–2392 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Jove, M. et al. Plasma lipidomics discloses metabolic syndrome with a specific HDL phenotype. FASEB J. 28, 5163–5171 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Holcˇapek, M. et al. Lipidomic analysis of plasma, erythrocytes and lipoprotein fractions of cardiovascular disease patients using UHPLC/MS, MALDI-MS and multivariate data analysis. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 990, 52–63 (2015).

    Article  CAS  Google Scholar 

  20. Camont, L. et al. Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities. Arterioscler. Thromb. Vasc. Biol. 33, 2715–2723 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Rached, F. et al. Defective functionality of small, dense HDL3 subpopulations in ST segment elevation myocardial infarction: relevance of enrichment in lysophosphatidylcholine, phosphatidic acid and serum amyloid A. Biochim. Biophys. Acta 1851, 1254–1261 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Rasmiena, A. A., Barlow, C. K., Ng, T. W., Tull, D. & Meikle, P. J. High density lipoprotein efficiently accepts surface but not internal oxidised lipids from oxidised low density lipoprotein. Biochim. Biophys. Acta 1861, 69–77 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. Prentki, M. & Madiraju, S. R. Glycerolipid metabolism and signaling in health and disease. Endocr. Rev. 29, 647–676 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Coleman, R. A. & Lee, D. P. Enzymes of triacylglycerol synthesis and their regulation. Prog. Lipid Res. 43, 134–176 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Perry, R. J., Samuel, V. T., Petersen, K. F. & Shulman, G. I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510, 84–91 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Finck, B. N. & Hall, A. M. Does diacylglycerol accumulation in fatty liver disease cause hepatic insulin resistance? Biomed. Res. Int. 2015, 104132 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Cole, L. K., Vance, J. E. & Vance, D. E. Phosphatidylcholine biosynthesis and lipoprotein metabolism. Biochim. Biophys. Acta 1821, 754–761 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Vance, J. E. & Vance, D. E. Phospholipid biosynthesis in mammalian cells. Biochem. Cell Biol. 82, 113–128 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Steenbergen, R. et al. Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects. J. Biol. Chem. 280, 40032–40040 (2005).

    Article  PubMed  CAS  Google Scholar 

  30. Selathurai, A. et al. The CDP–ethanolamine pathway regulates skeletal muscle diacylglycerol content and mitochondrial biogenesis without altering insulin sensitivity. Cell Metab. 21, 718–730 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Arendt, B. M. et al. Nonalcoholic fatty liver disease is associated with lower hepatic and erythrocyte ratios of phosphatidylcholine to phosphatidylethanolamine. Appl. Physiol. Nutr. Metab. 38, 334–340 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Fu, S. et al. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473, 528–531 (2011). A mechanistic study examining how obesity can lead to an increased ratio of phosphatidylcholine:phosphatidylethanolamine and subsequent endoplasmic reticulum stress.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Li, Z. et al. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis. Cell Metab. 3, 321–331 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Martínez-Uña, M. et al. Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis. Hepatology 58, 1296–1305 (2013). An elegant study demonstrating an important role of S -adenosylmethionine in phospholipid metabolism.

    Article  PubMed  CAS  Google Scholar 

  35. Song, J. et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J. 19, 1266–1271 (2005).

    Article  PubMed  CAS  Google Scholar 

  36. Dong, H. et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J. Hepatol. 46, 915–920 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Hebbard, L. & George, J. Animal models of nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 8, 35–44 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Jacobs, R. L., Devlin, C., Tabas, I. & Vance, D. E. Targeted deletion of hepatic CTP:phosphocholine cytidylyltransferase α in mice decreases plasma high density and very low density lipoproteins. J. Biol. Chem. 279, 47402–47410 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Walker, A. K. et al. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 147, 840–852 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Jacobs, R. L., van der Veen, J. N. & Vance, D. E. Finding the balance: the role of S-adenosylmethionine and phosphatidylcholine metabolism in development of nonalcoholic fatty liver disease. Hepatology 58, 1207–1209 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Lessig, J. & Fuchs, B. Plasmalogens in biological systems: their role in oxidative processes in biological membranes, their contribution to pathological processes and aging and plasmalogen analysis. Curr. Med. Chem. 16, 2021–2041 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Wallner, S. & Schmitz, G. Plasmalogens the neglected regulatory and scavenging lipid species. Chem. Phys. Lipids 164, 573–589 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Wu, L. C. et al. Purification, identification, and cloning of lysoplasmalogenase, the enzyme that catalyzes hydrolysis of the vinyl ether bond of lysoplasmalogen. J. Biol. Chem. 286, 24916–24930 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Meikle, P. J. et al. Plasma lipidomic analysis of stable and unstable coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 31, 2723–2732 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Goodenowe, D. B. et al. Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia. J. Lipid Res. 48, 2485–2498 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Wood, P. Circulating plasmalogen levels and Alzheimer Disease Assessment Scale–Cognitive scores in Alzheimer patients. J. Psychiatry Neurosci. 35, 59–62 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Mankidy, R. et al. Membrane plasmalogen composition and cellular cholesterol regulation: a structure activity study. Lipids Health Dis. 9, 62 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Maeba, R. et al. Plasmalogens in human serum positively correlate with high-density lipoprotein and decrease with aging. J. Atheroscler. Thromb. 14, 12–18 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Maeba, R. et al. Myo-inositol treatment increases serum plasmalogens and decreases small dense LDL, particularly in hyperlipidemic subjects with metabolic syndrome. J. Nutr. Sci. Vitaminol (Tokyo) 54, 196–202 (2008).

    Article  CAS  Google Scholar 

  50. Jürgens, G., Fell, A., Ledinski, G., Chen, Q. & Paltauf, F. Delay of copper-catalyzed oxidation of low density lipoprotein by in vitro enrichment with choline or ethanolamine plasmalogens. Chem. Phys. Lipids 77, 25–31 (1995).

    Article  PubMed  Google Scholar 

  51. Hajimoradi, M., Hassan, Z. M., Pourfathollah, A. A., Daneshmandi, S. & Pakravan, N. The effect of shark liver oil on the tumor infiltrating lymphocytes and cytokine pattern in mice. J. Ethnopharmacol. 126, 565–570 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Wentworth, J. M. et al. GM3 ganglioside and phosphatidylethanolamine-containing lipids are adipose tissue markers of insulin resistance in obese women. Int. J. Obes. (Lond.) 40, 706–713 (2016).

    Article  CAS  Google Scholar 

  53. Holland, W. L. & Summers, S. A. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr. Rev. 29, 381–402 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Holland, W. L. et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 5, 167–179 (2007). One of the first studies to characterize the relationship between ceramides, saturated fats and insulin resistance, and identify the enzymes involved as potential therapeutic targets.

    Article  CAS  PubMed  Google Scholar 

  55. Park, T. S. et al. Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice. Atherosclerosis 189, 264–272 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Hojjati, M. R. et al. Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. J. Biol. Chem. 280, 10284–10289 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Park, T. S. et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J. Lipid Res. 49, 2101–2112 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Eichler, F. S. et al. Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1. J. Neurosci. 29, 14646–14651 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Bertea, M. et al. Deoxysphingoid bases as plasma markers in diabetes mellitus. Lipids Health Dis. 9, 84 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Othman, A. et al. Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome? Diabetologia 55, 421–431 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Zuellig, R. A. et al. Deoxysphingolipids, novel biomarkers for type 2 diabetes, are cytotoxic for insulin-producing cells. Diabetes 63, 1326–1339 (2014). An important study providing a mechainistic framework for the role of deoxysphingolipids in type 2 diabetes mellitus.

    Article  CAS  PubMed  Google Scholar 

  62. Othman, A. et al. Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: a novel approach for treating diabetic neuropathy? J. Clin. Lipidol. 9, 568–575 (2015).

    Article  PubMed  Google Scholar 

  63. Chaurasia, B. & Summers, S. A. Ceramides — lipotoxic inducers of metabolic disorders. Trends Endocrinol. Metab. 26, 538–550 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Chavez, J. A. et al. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J. Biol. Chem. 278, 10297–10303 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Stratford, S., DeWald, D. B. & Summers, S. A. Ceramide dissociates 3′-phosphoinositide production from pleckstrin homology domain translocation. Biochem. J. 354, 359–368 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Summers, S. A., Garza, L. A., Zhou, H. & Birnbaum, M. J. Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol. Cell. Biol. 18, 5457–5464 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Chavez, J. A. et al. Ceramides and glucosylceramides are independent antagonists of insulin signaling. J. Biol. Chem. 289, 723–734 (2014).

    Article  PubMed  CAS  Google Scholar 

  68. Zhang, Q. J. et al. Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS–Akt complex. Diabetes 61, 1848–1859 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Bikman, B. T. et al. Fenretinide prevents lipid-induced insulin resistance by blocking ceramide biosynthesis. J. Biol. Chem. 287, 17426–17437 (2012). A study identifying Des1 as a potential therapeutic target for glucose homeostasis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Chun, L. et al. Inhibition of ceramide synthesis reverses endothelial dysfunction and atherosclerosis in streptozotocin-induced diabetic rats. Diabetes Res. Clin. Pract. 93, 77–85 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Park, T. S., Rosebury, W., Kindt, E. K., Kowala, M. C. & Panek, R. L. Serine palmitoyltransferase inhibitor myriocin induces the regression of atherosclerotic plaques in hyperlipidemic ApoE-deficient mice. Pharmacol. Res. 58, 45–51 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Glaros, E. N. et al. Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice. J. Lipid Res. 49, 324–331 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Glaros, E. N. et al. Inhibition of atherosclerosis by the serine palmitoyl transferase inhibitor myriocin is associated with reduced plasma glycosphingolipid concentration. Biochem. Pharmacol. 73, 1340–1346 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Park, T. S. & Goldberg, I. J. Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure. Heart Fail. Clin. 8, 633–641 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Jiang, X. C., Goldberg, I. J. & Park, T. S. Sphingolipids and cardiovascular diseases: lipoprotein metabolism, atherosclerosis and cardiomyopathy. Adv. Exp. Med. Biol. 721, 19–39 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Holland, W. L. et al. An FGF21–adiponectin–ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 17, 790–797 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Holland, W. L. et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat. Med. 17, 55–63 (2011).

    CAS  PubMed  Google Scholar 

  78. Lopez, X., Goldfine, A. B., Holland, W. L., Gordillo, R. & Scherer, P. E. Plasma ceramides are elevated in female children and adolescents with type 2 diabetes. J. Pediatr. Endocrinol. Metab. 26, 995–998 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Haus, J. M. et al. Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes 58, 337–343 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Warshauer, J. T. et al. Effect of pioglitazone on plasma ceramides in adults with metabolic syndrome. Diabetes Metab. Res. Rev. 31, 734–744 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Bergman, B. C. et al. Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans. Am. J. Physiol. Endocrinol. Metab. 309, E398–E408 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Amati, F. et al. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes 60, 2588–2597 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Coen, P. M. et al. Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity. Obesity (Silver Spring) 21, 2362–2371 (2013).

    Article  CAS  Google Scholar 

  84. de la Maza, M. P. et al. Skeletal muscle ceramide species in men with abdominal obesity. J. Nutr. Health Aging 19, 389–396 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Coen, P. M. et al. Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content. Diabetes 59, 80–88 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Adams, J. M. et al. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 53, 25–31 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Skovbro, M. et al. Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity. Diabetologia 51, 1253–1260 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Petersen, M. C. & Jurczak, M. J. CrossTalk opposing view: intramyocellular ceramide accumulation does not modulate insulin resistance. J. Physiol. 594, 3171–3174 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Summers, S. A. & Goodpaster, B. H. CrossTalk proposal: intramyocellular ceramide accumulation does modulate insulin resistance. J. Physiol. 594, 3167–3170 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Turpin, S. M. et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 20, 678–686 (2014). One of a series of studies to differentiate the roles of CerS isoforms in insulin resistance.

    Article  PubMed  CAS  Google Scholar 

  91. Raichur, S. et al. CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 20, 687–695 (2014). The second in a series of papers in this edition to address the specific role of CerS isoforms in insulin resistance.

    Article  CAS  PubMed  Google Scholar 

  92. Hla, T. & Kolesnick, R. C16:0-ceramide signals insulin resistance. Cell Metab. 20, 703–705 (2014). An editorial covering the two previous articles and highlighting the specific role of C16:0 ceramide in insulin resistance.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Gosejacob, D. et al. Ceramide synthase 5 is essential to maintain C16:0-ceramide pools and contributes to the development of diet-induced obesity. J. Biol. Chem. 291, 6989–7003 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Luukkonen, P. K. et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J. Hepatol. 64, 1167–1175 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. Bergman, B. C. et al. Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans. Diabetologia 59, 785–798 (2016). An important study that characterises the specific role of C18:0 ceramide in insulin resistance in skeletal muscle.

    Article  CAS  PubMed  Google Scholar 

  96. Hanamatsu, H. et al. Altered levels of serum sphingomyelin and ceramide containing distinct acyl chains in young obese adults. Nutr. Diabetes 4, e141 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Martinez-Ramirez, M. et al. HDL-sphingomyelin reduction after weight loss by an energy-restricted diet is associated with the improvement of lipid profile, blood pressure, and decrease of insulin resistance in overweight/obese patients. Clin. Chim. Acta 454, 77–81 (2016). An important human study that links alterations in sphingolipid metabolism resulting from a dietary intervention to a decrease in insulin resistance.

    Article  CAS  PubMed  Google Scholar 

  98. Li, Z. et al. Reducing plasma membrane sphingomyelin increases insulin sensitivity. Mol. Cell. Biol. 31, 4205–4218 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Sugimoto, M. et al. Characterization of the role of sphingomyelin synthase 2 in glucose metabolism in whole-body and peripheral tissues in mice. Biochim. Biophys. Acta 1861, 688–702 (2016).

    Article  CAS  PubMed  Google Scholar 

  100. Fan, Y. et al. Selective reduction in the sphingomyelin content of atherogenic lipoproteins inhibits their retention in murine aortas and the subsequent development of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 30, 2114–2120 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Aerts, J. M. et al. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56, 1341–1349 (2007).

    Article  PubMed  CAS  Google Scholar 

  102. Zhao, H. et al. Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes 56, 1210–1218 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Zhao, H. et al. Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice. Hepatology 50, 85–93 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Chatterjee, S. et al. Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in apolipoprotein E−/− mice and rabbits fed a high-fat and -cholesterol diet. Circulation 129, 2403–2413 (2014). A study demonstrating the therapeutic potential of the regulation of glycosphingolipid synthesis to attenuate atherosclerosis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Bietrix, F. et al. Inhibition of glycosphingolipid synthesis induces a profound reduction of plasma cholesterol and inhibits atherosclerosis development in APOE*3 Leiden and low-density lipoprotein receptor−/− mice. Arterioscler. Thromb. Vasc. Biol. 30, 931–937 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Glaros, E. N., Kim, W. S., Rye, K. A., Shayman, J. A. & Garner, B. Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice. J. Lipid Res. 49, 1677–1681 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Inokuchi, J. Insulin resistance as a membrane microdomain disorder. Yakugaku Zasshi 127, 579–586 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Tagami, S. et al. Ganglioside GM3 participates in the pathological conditions of insulin resistance. J. Biol. Chem. 277, 3085–3092 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Yamashita, T. et al. Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc. Natl Acad. Sci. USA 100, 3445–3449 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ussher, J. R. et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59, 2453–2464 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Murphy, M. P. Mitochondrial dysfunction indirectly elevates ROS production by the endoplasmic reticulum. Cell Metab. 18, 145–146 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. de Mello, V. D. et al. Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease. Diabetologia 52, 2612–2615 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Majumdar, I. & Mastrandrea, L. D. Serum sphingolipids and inflammatory mediators in adolescents at risk for metabolic syndrome. Endocrine 41, 442–449 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Caballero, F. et al. Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-l-methionine and glutathione. J. Biol. Chem. 285, 18528–18536 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Mato, J. M. & Lu, S. C. Role of S-adenosyl-l-methionine in liver health and injury. Hepatology 45, 1306–1312 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Cano, A. et al. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice. Hepatology 54, 1975–1986 (2011).

    Article  PubMed  CAS  Google Scholar 

  117. Moylan, C. A. et al. Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatology 59, 471–482 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Brites, P. et al. Alkyl-glycerol rescues plasmalogen levels and pathology of ether-phospholipid deficient mice. PLoS ONE 6, e28539 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Das, A. K., Holmes, R. D., Wilson, G. N. & Hajra, A. K. Dietary ether lipid incorporation into tissue plasmalogens of humans and rodents. Lipids 27, 401–405 (1992).

    Article  CAS  PubMed  Google Scholar 

  120. Marigny, K. et al. Modulation of endothelial permeability by 1-O-alkylglycerols. Acta Physiol. Scand. 176, 263–268 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Pédrono, F., Saïag, B., Moulinoux, J. P. & Legrand, A. B. 1-O-alkylglycerols reduce the stimulating effects of bFGF on endothelial cell proliferation in vitro. Cancer Lett. 251, 317–322 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Zhang, M., Sun, S., Tang, N., Cai, W. & Qian, L. Oral administration of alkylglycerols differentially modulates high-fat diet-induced obesity and insulin resistance in mice. Evid. Based Complement. Alternat. Med. 2013, 834027 (2013).

    PubMed  PubMed Central  Google Scholar 

  123. Rasmiena, A. A. et al. Plasmalogen modulation attenuates atherosclerosis in ApoE- and ApoE/GPx1-deficient mice. Atherosclerosis 243, 598–608 (2015). The first and only demonstration of plasmalogen modulation as a therapetic strategy in atherosclerosis.

    Article  CAS  PubMed  Google Scholar 

  124. Iannitti, T. & Palmieri, B. An update on the therapeutic role of alkylglycerols. Mar. Drugs 8, 2267–2300 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Wood, P. L., Khan, M. A., Mankidy, R., Smith, T. & Goodenowe, D. B. in Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets Ch. 24 (ed. De La Monte, S.) 561–588 (InTech, 2011).

    Google Scholar 

  126. Wood, P. L. et al. Oral bioavailability of the ether lipid plasmalogen precursor, PPI-1011, in the rabbit: a new therapeutic strategy for Alzheimer's disease. Lipids Health Dis. 10, 227 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Grégoire, L. et al. Plasmalogen precursor analog treatment reduces levodopa-induced dyskinesias in parkinsonian monkeys. Behav. Brain Res. 286, 328–337 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Miville-Godbout, E. et al. Plasmalogen augmentation reverses striatal dopamine loss in MPTP mice. PLoS ONE 11, e0151020 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Kien, C. L. et al. A lipidomics analysis of the relationship between dietary fatty acid composition and insulin sensitivity in young adults. Diabetes 62, 1054–1063 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Lankinen, M. et al. A healthy nordic diet alters the plasma lipidomic profile in adults with features of metabolic syndrome in a multicenter randomized dietary intervention. J. Nutr. 146, 662–672 (2016).

    Article  CAS  Google Scholar 

  131. Coen, P. M. et al. Exercise and weight loss improve muscle mitochondrial respiration, lipid partitioning, and insulin sensitivity after gastric bypass surgery. Diabetes 64, 3737–3750 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Bikman, B. T. & Summers, S. A. Ceramides as modulators of cellular and whole-body metabolism. J. Clin. Invest. 121, 4222–4230 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Chavez, J. A. & Summers, S. A. A ceramide-centric view of insulin resistance. Cell Metab. 15, 585–594 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Wang, S. et al. Simultaneous determination of nucleosides, myriocin, and carbohydrates in Cordyceps by HPLC coupled with diode array detection and evaporative light scattering detection. J. Sep. Sci. 32, 4069–4076 (2009).

    Article  CAS  PubMed  Google Scholar 

  135. Yu, J., Xu, H., Mo, Z., Zhu, H. & Mao, X. Determination of myriocin in natural and cultured Cordyceps cicadae using 9-fluorenylmethyl chloroformate derivatization and high-performance liquid chromatography with UV-detection. Anal. Sci. 25, 855–859 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Yu, S. H. et al. Hypoglycemic activity through a novel combination of fruiting body and mycelia of Cordyceps militaris in high-fat diet-induced type 2 diabetes mellitus mice. J. Diabetes Res. 2015, 723190 (2015).

    PubMed  PubMed Central  Google Scholar 

  137. Dong, Y. et al. Studies on the antidiabetic activities of Cordyceps militaris extract in diet-streptozotocin-induced diabetic Sprague-Dawley rats. Biomed. Res. Int. 2014, 160980 (2014).

    PubMed  PubMed Central  Google Scholar 

  138. Zhang, H. W. et al. Cordyceps sinensis (a traditional Chinese medicine) for treating chronic kidney disease. Cochrane Database Syst. Rev. 12, CD008353 (2014).

    Google Scholar 

  139. Mody, N. & McIlroy, G. D. The mechanisms of fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes. Biochem. Pharmacol. 91, 277–286 (2014).

    Article  CAS  PubMed  Google Scholar 

  140. Siddique, M. M., Li, Y., Chaurasia, B., Kaddai, V. A. & Summers, S. A. Dihydroceramides: from bit players to lead actors. J. Biol. Chem. 290, 15371–15379 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Veronesi, U. et al. Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Ann. Oncol. 17, 1065–1071 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Zanardi, S. et al. Clinical trials with retinoids for breast cancer chemoprevention. Endocr. Relat. Cancer 13, 51–68 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Sabichi, A. L. et al. Phase III prevention trial of fenretinide in patients with resected non-muscle-invasive bladder cancer. Clin. Cancer Res. 14, 224–229 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Aerts, J. M. et al. Glycosphingolipids and insulin resistance. Adv. Exp. Med. Biol. 721, 99–119 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Bennett, L. L. & Turcotte, K. Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease. Drug Des. Devel. Ther. 9, 4639–4647 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Shayman, J. A. Developing novel chemical entities for the treatment of lysosomal storage disorders: an academic perspective. Am. J. Physiol. Renal Physiol. 309, F996–F999 (2015).

    Article  CAS  PubMed  Google Scholar 

  147. Shayman, J. A. The design and clinical development of inhibitors of glycosphingolipid synthesis: will invention be the mother of necessity? Trans. Am. Clin. Climatol. Assoc. 124, 46–60 (2013).

    PubMed  PubMed Central  Google Scholar 

  148. Yang, G. et al. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am. J. Physiol. Endocrinol. Metab. 297, E211–E224 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Kurek, K. et al. Inhibition of ceramide de novo synthesis ameliorates diet induced skeletal muscles insulin resistance. J. Diabetes Res. 2015, 154762 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Dekker, M. J. et al. Inhibition of sphingolipid synthesis improves dyslipidemia in the diet-induced hamster model of insulin resistance: evidence for the role of sphingosine and sphinganine in hepatic VLDL-apoB100 overproduction. Atherosclerosis 228, 98–109 (2013).

    Article  CAS  PubMed  Google Scholar 

  151. Chakraborty, M. et al. Myeloid cell-specific serine palmitoyltransferase subunit 2 haploinsufficiency reduces murine atherosclerosis. J. Clin. Invest. 123, 1784–1797 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Kasumov, T. et al. Ceramide as a mediator of non-alcoholic fatty liver disease and associated atherosclerosis. PLoS ONE 10, e0126910 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Kurek, K. et al. Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease. Liver Int. 34, 1074–1083 (2014).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

P.J.M. is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia.

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed equally to the researching data for the article, discussion of the content, writing the article and reviewing and/or editing the article before submission.

Corresponding author

Correspondence to Peter J. Meikle.

Ethics declarations

Competing interests

P.J.M. declares no competing interests. S.A.S. is co-founder and scientific adviser of Centaurus Therapeutics Inc.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meikle, P., Summers, S. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat Rev Endocrinol 13, 79–91 (2017). https://doi.org/10.1038/nrendo.2016.169

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2016.169

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing