Ukr.Biochem.J. 2024; Volume 96, Issue 2, Mar-Apr, pp. 84-99


Diet-induced and age-related changes in rats: the impact of N-stearoylethanolamine intake on plasma lipoproteins, adiponectin, and adipocyte cholesterol-phospholipid composition

O. S. Tkachenko*, H. V. Kosiakova

Palladin Institute of Biochemistry,
National Academy of Sciences of Ukraine, Kyiv, Ukraine;

Received: 26 January 2024; Revised: 19 March 2024;
Accepted: 19 March 2024; Available on-line: 30 April 2024

Adiponectin is secreted by adipose tissue, associated with lipoprotein (LP) metabolism, down-regulated­ in insulin resistance states, and reduced in individuals suffering from obesity and cardiovascular diseases. Phospholipids and cholesterol are the main components of cell membranes and play a critical role in storage and secretory adipocyte functions. N-stearoylethanolamine (NSE) is a minor lipid affecting cell membrane lipids’ composition. Our study aimed to investigate plasma levels of adiponectin and cholesterol of low- and high-density LP (LDL and HDL) and adipocyte cholesterol-phospholipid (Chol-PL) composition of different age rats with high-fat diet (HFD)-induced obesity and insulin resistance and their changes under NSE administration. Our study demonstrated that chronic dietary fat overloading leads to obesity accompanied by impairment of glucose tolerance, a manifestation of dyslipidemia, and changes in plasma adiponectin levels in rats from two age groups (10-month-old and and 24-month-old). Prolonged HFD led to a reduction in plasma adiponectin levels and the growth of adipocyte cholesterol content in rats of different ages. A significant increase in plasma LDL-Chol level and main adipocyte PLs (phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine) was observed in younger rats, whereas not detected in elder animals after dietary fats overloading. The decrease in the content of anionic phospholipids (phosphatidylinositol + phosphatidylserine) was also detected in 10-month-old HFD rats compared to the control animals. NSE administration positively affected the normalization of adiponectin levels in both age HFD groups. It significantly impacted the reduction of LDL-Chol levels and the growth of HDL-Chol concentration in the blood plasma of 10-month-old rats as well as PL-composition of young HFD rats and anionic PL restoring in 24-month-old rats. The positive effect on investigated parameters makes NSE a prospective agent for treating diet-induced and age-related metabolic disorders threatening cardiovascular diseases.

Keywords: , , , , , , ,


  1. Powell-Wiley TM, Poirier P, Burke LE, Després JP, Gordon-Larsen P, Lavie CJ, Lear SA, Ndumele CE, Neeland IJ, Sanders P, St-Onge MP. Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2021;143(21):e984-e1010. PubMed, PubMedCentral, CrossRef
  2. Stadler JT, Marsche G. Obesity-Related Changes in High-Density Lipoprotein Metabolism and Function. Int J Mol Sci. 2020;21(23):8985. PubMed, PubMedCentral, CrossRef
  3. Stadler JT, Lackner S, Mörkl S, Trakaki A, Scharnagl H, Borenich A, Wonisch W, Mangge H, Zelzer S, Meier-Allard N, Holasek SJ, Marsche G. Obesity Affects HDL Metabolism, Composition and Subclass Distribution. Biomedicines. 2021;9(3):242. PubMed, PubMedCentral, CrossRef
  4. Dziuba OS, Chernyshenko VO, Hudz IeA, Kasatkina LO, Chernyshenko TM, Klymenko PP, Kosiakova HV, Platonova TM, Hula NM, Lugovskoy EV. Blood coagulation and aortic wall integrity in rats with obesity-induced insulin resistance. Ukr Biochem J. 2018;90(2):14-23. CrossRef
  5. Tchoukalova YD, Sarr MG, Jensen MD. Measuring committed preadipocytes in human adipose tissue from severely obese patients by using adipocyte fatty acid binding protein. Am J Physiol Regul Integr Comp Physiol. 2004;287(5):R1132-R1140. PubMed, CrossRef
  6. Elgazar-Carmon V, Rudich A, Hadad N, Levy R. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res. 2008;49(9):1894-1903. PubMed, CrossRef
  7. Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M, Fischer-Posovszky P, Barth TF, Dragun D, Skurk T, Hauner H, Blüher M, Unger T, Wolf AM, Knippschild U, Hombach V, Marx N. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler Thromb Vasc Biol. 2008;28(7):1304-1310. PubMed, PubMedCentral, CrossRef
  8. Satoshi Hirako. Adiponectin. Handbook of Hormones (Second Edition). Academic Press, 2021. P. 577-579. CrossRef
  9. Li X, Zhang D, Vatner DF, Goedeke L, Hirabara SM, Zhang Y, Perry RJ, Shulman GI. Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice. Proc Natl Acad Sci USA. 2020;117(51):32584-32593. PubMed, PubMedCentral, CrossRef
  10. Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, Pang Z, Chen AS, Ruderman NB, Chen H, Rossetti L, Scherer PE. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem. 2006;281(5):2654-2660. PubMed, CrossRef
  11. Xia JY, Sun K, Hepler C, Ghaben AL, Gupta RK, An YA, Holland WL, Morley TS, Adams AC, Gordillo R, Kusminski CM, Scherer PE. Acute loss of adipose tissue-derived adiponectin triggers immediate metabolic deterioration in mice. Diabetologia. 2018;61(4):932-941. PubMed, PubMedCentral, CrossRef
  12. Li N, Zhao S, Zhang Z, Zhu Y, Gliniak CM, Vishvanath L, An YA, Wang MY, Deng Y, Zhu Q, Shan B, Sherwood A, Onodera T, Oz OK, Gordillo R, Gupta RK, Liu M, Horvath TL, Dixit VD, Scherer PE. Adiponectin preserves metabolic fitness during aging. Elife. 2021;10:e65108. PubMed, PubMedCentral, CrossRef
  13. Manual Kollareth DJ, Chang CL, Zirpoli H, Deckelbaum RJ. Chapter 21 – Molecular mechanisms underlying effects of n−3 and n−6 fatty acids in cardiovascular diseases. Ed. Ntambi JM. Lipid Signaling and Metabolism. Academic Press, 2020. P. 427-453. CrossRef
  14. Laclaustra M, Lopez-Garcia E, Civeira F, Garcia-Esquinas E, Graciani A , Guallar-Castillon P, Banegas JR, Rodriguez-Artalejo F. LDL Cholesterol Rises With BMI Only in Lean Individuals: Cross-sectional U.S. and Spanish Representative Data. Diabetes Care. 2018;41(10):2195-2201. PubMed, CrossRef
  15. Chui PC, Guan HP, Lehrke M, Lazar MA. PPARgamma regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1. J Clin Invest. 2005;115(8):2244-2256. PubMed, PubMedCentral, CrossRef
  16. Chang W, Hatch GM, Wang Y, Yu F, Wang M. The relationship between phospholipids and insulin resistance: From clinical to experimental studies. J Cell Mol Med. 2019;23(2):702-710. PubMed, PubMedCentral, CrossRef
  17. Kosiakova GV, Gula NM. The N-stearoylethanolamine effect on the NO-synthase way of nitrogen oxide formation and phospholipid composition of erythrocyte membranes in rats with streptozotocine diabetes. Ukr Biokhim Zhurn. 2007;79(6):53-59. (In Ukrainian). PubMed
  18. Goridko TM, Gula NM, Stogniy NA, Meged OF, Klimashevsky VM, Shovkun SA, Kindruk NL, Berdyshev AG. Influence of N- stearoylethanolamine on the lipid peroxidation process and lipid composition of the rat liver under acute morphine intoxication. Ukr Biokhim Zhurn. 2007;79(5):175-185. (In Ukrainian). PubMed
  19. Gula NM, Chumak AA, Berdyshev AG, Meged EF, Goridko TM, Kindruk NL, Kosyakova GV, Zhukov OD. Anti-inflammatory effect of N-stearoylethanolamine in experimental burn injury in rats. Ukr Biokhim Zhurn. 2009;81(2):107-116. (In Ukrainian). PubMed
  20. Goridko TM, Kosiakova GV, Berdyschev AG, Bazylyanska VR, Margitich VM, Gula NM. The influence of N-stearoylethanolamine on the activity of antioxidant enzymes and on the level of stable NO metabolites in the rat testes and blood plasma at the early stages of streptozotocine-induced diabetes. Ukr Biokhim Zhurn. 2012;84(3):37-43. (In Ukrainia). PubMed
  21. Onopchenko OV, Kosiakova GV, Goridko TM, Klimashevsky VM, Hula NM. The effect of N-stearoylethanolamine on liver phospholipid composition of rats with insulin resistance caused by alimentary obesity. Ukr Biochem J. 2014;86(1):101-110. (In Ukrainian). CrossRef
  22. Onopchenko OV, Kosiakova GV, Oz M, Klimashevsky VM, Gula NM. N-stearoylethanolamine restores pancreas lipid composition in obesity-induced insulin resistant rats. Lipids. 2015;50(1):13-21. PubMed, CrossRef
  23. Onopchenko OV, Kosiakova GV, Meged EF, Klimashevsky VM, Hula NM. The effect of N-stearoylethanolamine on cholesterol content, fatty acid composition and protein carbonylation level in rats with alimentary obesity-induced insulin resistance. Ukr Biochem J. 2014;86(6):119-128. PubMed, CrossRef
  24. Tkachenko O, Kosiakova H, Klimashevsky V, Berdyshev A, Hula N. The Effect of N-Stearoylethanolamine on the Adipocyte Fatty Acid Composition of Different Age Rats with Obesity-Induced Insulin Resistance. Eureca: Life Sci. 2020;(2):10-23. CrossRef
  25. Tkachenko OS, Hudz IeA, Kosiakova HV, Klymenko PP, Stohnii YM, Didkivskyi VA, Chernyshenko TM, Chernyshenko VO, Platonova TM. Protective action of N-stearoylethanolamine on blood coagulation and arterial changes in spontaneously hypertensive rats fed cholesterol-rich diet. Ukr Biochem J. 2020;92(2):60-70. CrossRef
  26. Collier GR, Chisholm K, Sykes S, Dryden PA, O’Dea K. More severe impairment of oral than intravenous glucose tolerance in rats after eating a high fat diet. J Nutr. 1985;115(11):1471-1476. PubMed, CrossRef
  27. Epps DE, Natarajan V, Schmid PC, Schmid HO. Accumulation of N-acylethanolamine glycerophospholipids in infarcted myocardium. Biochim Biophys Acta. 1980;618(3):420-430. PubMed, CrossRef
  28. Rodbell M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem. 1964;239:375-380. PubMed
  29. Mueller WM, Gregoire FM, Stanhope KL, Mobbs CV, Mizuno TM, Warden CH, Stern JS, Havell PJ. Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes. Endocrinology. 1998;139(2):551-558. PubMed, CrossRef
  30. Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37(8):911-917. PubMed, CrossRef
  31. Vaskovsky VE, Terekhova TA. HPTLC of phospholipid mixtures containing phosphatidylglycerol. J High Resolut Chromatogr Chromatogr Commun. 1979;2:671-672. CrossRef
  32. Svetashev VI, Vaskovsky VE. A simplified technique for thin-layer microchromatography of lipids. J Chromatogr. 1972;67(2):376-378. PubMed, CrossRef
  33. Vaskovsky VE, Kostetsky EY, Vasendin IM. A universal reagent for phospholipid analysis. J Chromatogr. 1975;114(1):129-141. PubMed, CrossRef
  34. Cerqueira NM, Oliveira EF, Gesto DS, Santos-Martins D, Moreira C, Moorthy HN, Ramos MJ, Fernandes PA. Cholesterol Biosynthesis: A Mechanistic Overview. Biochemistry. 2016;55(39):5483-5506. PubMed, CrossRef
  35. Hussain MM, Strickland DK, Bakillah A. The mammalian low-density lipoprotein receptor family. Annu Rev Nutr. 1999;19:141-172. PubMed, , CrossRef
  36. Ouimet M, Barrett TJ, Fisher EA. HDL and Reverse Cholesterol Transport. Circ Res. 2019;124(10):1505-1518. PubMed, PubMedCentral, CrossRef
  37. Wilson PW, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortality. The Framingham Heart Study. Arteriosclerosis. 1988;8(6):737-741. PubMed, CrossRef
  38. Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet. 2014;384(9943):618-625. PubMed, CrossRef
  39. Favari E, Chroni A, Tietge UJF, Zanotti I, Escolà-Gil JC, Bernini F. Cholesterol efflux and reverse cholesterol transport. Handb Exp Pharmacol. 2015;224:181-206. PubMed, CrossRef
  40. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017;38(32):2478-2486. PubMed, CrossRef
  41. Rodriguez A. High HDL-Cholesterol Paradox: SCARB1-LAG3-HDL Axis. Curr Atheroscler Rep. 2021;23(1):5. PubMed, PubMedCentral, CrossRef
  42. Mc Auley MT. Effects of obesity on cholesterol metabolism and its implications for healthy ageing. Nutr Res Rev. 2020;33(1):121-133. PubMed, CrossRef
  43. Van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9(2):112-124. PubMed, PubMedCentral, CrossRef
  44. Wang Y, Wang X, Lau WB, Yuan Y, Booth D, Li JJ, Scalia R, Preston K, Gao E, Koch W, Ma XL. Adiponectin inhibits tumor necrosis factor-α-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation. Circ Res. 2014;114(5):792-805. PubMed, PubMedCentral, CrossRef
  45. Yu H, Gao X, Ge Q, Tai W, Hao X, Shao Q, Fang Z, Chen M, Song Y, Gao W, Liu G, Du X, Li X. Tumor necrosis factor-α reduces adiponectin production by decreasing transcriptional activity of peroxisome proliferator-activated receptor-γ in calf adipocytes. J Dairy Sci. 2023l;106(7):5182-5195. PubMed, CrossRef
  46. Berdyshev AG, Kosiakova HV, Onopchenko OV, Panchuk RR, Stoika RS, Hula NM. N-Stearoylethanolamine suppresses the pro-inflammatory cytokines production by inhibition of NF-κB translocation. Prostaglandins Other Lipid Mediat. 2015;121(Pt A):91-96. PubMed, CrossRef
  47. Onopchenko OV, Kosiakova GV, Klimashevsky VM, Hula NM. The effect of N-stearoylethanolamine on plasma lipid composition in rats with experimental insulin resistance. Ukr Biochem J. 2015;87(1):46-54. PubMed, CrossRef
  48. Onopchenko OV, Kosiakova GV, Goridko TM, Berdyshev AG, Mehed OF, Hula NM. The effect of N-stearoylethanolamine on the activity of antioxidant enzymes, content of lipid peroxidation products and nitric oxide in the blood plasma and liver of rats with induced insulin-resistance. Ukr Biokhim Zhurn. 2013;85(5): 88-96. (In Ukrainian). PubMed, CrossRef
  49. ousset X, Vaisman B, Amar M, Sethi AA, Remaley AT. Lecithin: cholesterol acyltransferase – from biochemistry to role in cardiovascular disease. Curr Opin Endocrinol Diabetes Obes. 2009;16(2):163-171. PubMed, PubMedCentral, CrossRef
  50. Yeagle PL. Cholesterol and the cell membrane. Biochim Biophys Acta. 1985;822(3-4):267-287. PubMed, CrossRef
  51. Yeagle PL. Modulation of membrane function by cholesterol. Biochimie. 1991;73(10):1303-1310. PubMed, CrossRef
  52. Esteve Ràfols M. Adipose tissue: cell heterogeneity and functional diversity. Endocrinol Nutr. 2014;61(2):100-112. PubMed, CrossRef
  53. Kennedy EP, Weiss SB. The function of cytidine coenzymes in the biosynthesis of phospholipides. J Biol Chem. 1956;222(1):193-214. PubMed, CrossRef
  54. Zeghari N, Younsi M, Meyer L, Donner M, Drouin P, Ziegler O. Adipocyte and erythrocyte plasma membrane phospholipid composition and hyperinsulinemia: a study in nondiabetic and diabetic obese women. Int J Obes Relat Metab Disord. 2000;24(12):1600-1607. PubMed, CrossRef
  55. Krahmer N, Guo Y, Wilfling F, Hilger M, Lingrell S, Heger K, Newman HW, Schmidt-Supprian M, Vance DE, Mann M, Farese RV Jr, Walther TC. Phosphatidylcholine synthesis for lipid droplet expansion is mediated by localized activation of CTP:phosphocholine cytidylyltransferase. Cell Metab. 2011;14(4):504-515. PubMed, PubMedCentral, CrossRef
  56. Macaulay SL, Larkins RG. Insulin stimulates turnover of phosphatidylcholine in rat adipocytes. Mol Cell Biochem. 1994;136(1):23-28. PubMed, CrossRef
  57. Donchenko V, Zannetti A, Baldini PM. Insulin-stimulated hydrolysis of phosphatidylcholine by phospholipase C and phospholipase D in cultured rat hepatocytes. Biochim Biophys Acta. 1994;1222(3):492-500. PubMed, CrossRef
  58. Cazzolli R., Huang P, Teng S, Hughes WE. Measuring phospholipase D activity in insulin-secreting pancreatic beta-cells and insulin-responsive muscle cells and adipocytes. Methods Mol Biol. 2009;462:241-251. PubMed, CrossRef
  59. Kurauti MA, Ferreira SM, Soares GM, Vettorazzi JF, Carneiro EM, Boschero AC, Costa-Júnior JM. Hyperinsulinemia is associated with increasing insulin secretion but not with decreasing insulin clearance in an age-related metabolic dysfunction mice model. J Cell Physiol. 2019;234(6):9802-9809. PubMed, CrossRef
  60. LeRoith D, Taylor SI, Olefsky JM. Diabetes mellitus: a fundamental and clinical text. Lippincott Williams & Wilkins, 2004. P. 303.
  61. Petkova DH, Momchilova AB, Koumanov KS. Age-related changes in rat liver plasma membrane phospholipase A2 activity. Exp Gerontol. 1986;21(3):187-193. PubMed, CrossRef
  62. Zolese G, Wozniak M, Mariani P, Saturni L, Bertoli E, Ambrosini A. Different modulation of phospholipase A2 activity by saturated and monounsaturated N-acylethanolamines. J Lipid Res. 2003;44(4):742-753. PubMed, CrossRef
  63. Severson DL, Hurley B. Stimulation of the hormone-sensitive triacylglycerol lipase from adipose tissue by phosphatidylethanolamine. Biochim Biophys Acta. 1985;845(2):283-291. PubMed, CrossRef
  64. an der Veen JN, Kennelly JP, Wan S, Vance JE, Vance DE, Jacobs RL. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim Biophys Acta Biomembr. 2017;1859(9 Pt B):1558-1572. PubMed, CrossRef
  65. avrilova NJ, Setchenska MS, Markovska TT, Momchilova-Pankova AB, Koumanov KS. Effect of membrane phospholipid composition and fluidity on rat liver plasma membrane tyrosine kinase activity. Int J Biochem. 1993;25(9):1309-1312. PubMed, CrossRef
  66. Torretta E, Barbacini P, Al-Daghri NM, Gelfi C. Sphingolipids in Obesity and Correlated Co-Morbidities: The Contribution of Gender, Age and Environment. Int J Mol Sci. 2019;20(23):5901. PubMed, PubMedCentral, CrossRef
  67. Mosior M, Newton AC. Mechanism of the apparent cooperativity in the interaction of protein kinase C with phosphatidylserine. Biochemistry. 1998;37(49):17271-17279. PubMed, CrossRef
  68. 68. Bandyopadhyay G, Sajan MP, Kanoh Y, Standaert ML, Quon MJ, Lea-Currie R, Sen A, Farese RV. PKC-zeta mediates insulin effects on glucose transport in cultured preadipocyte-derived human adipocytes. J Clin Endocrinol Metab. 2002;87(2):716-723.  PubMed, CrossRef
  69. Sweet LJ, Dudley DT, Pessin JE, Spector AA. Phospholipid activation of the insulin receptor kinase: regulation by phosphatidylinositol. FASEB J. 1987;1(1):55-59. PubMed, CrossRef
  70. Kosiakova H, Berdyshev A, Dosenko V, Drevytska T, Herasymenko O, Hula N. The involvement of peroxisome proliferator-activated receptor gamma (PPARγ) in anti-inflammatory activity of N-stearoylethanolamine. Heliyon. 2022;8(11):e11336. PubMed, PubMedCentral, CrossRef
  71. Gula NM, Chumak AA, Mehed OF, Goridko TM, Kindruk NL, Berdyshev AH. Immunosuppressive characteristics of N-stearoylethanolamine a stable compound with cannabimimetic activity. Ukr Biokhim Zhurn. 2008;80(1): 57-67. (In Ukrainian).

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