Insulin Resistance and Non-alcoholic Fatty Liver Disease Induced by Conjugated Linoleic Acid in Humans

  • Madhuri Vemuri
  • Darshan S. KelleyEmail author
Part of the Nutrition and Health book series (NH)

Key Points

• Mixed isomers of conjugated linoleic acid and purified t10, c12-CLA decreased body weight and body fat mass in animal models but not humans.

• Conjugated linoleic acid supplementation in humans have been shown to cause insulin resistance and fatty liver. Because of lack of any significant health benefit from CLA consumption and its associated risks on insulin resistance and fatty liver, this natural or synthetic group of fatty acids cannot be recommended as a supplement that can be used to improve human health.


Conjugated linoleic acid Insulin resistance Diabetes Fatty liver 


  1. 1.
    Banni S. Conjugated linoleic acid metabolism. Curr Opin Lipidol 2002; 13: 261–266.PubMedCrossRefGoogle Scholar
  2. 2.
    Bhattacharya A, Banu J, Rahman M, Causey J, Fernandes G. Biological effects of conjugated linoleic acids in health and disease. J Nutr Biochem 2006; 17: 789–810.PubMedCrossRefGoogle Scholar
  3. 3.
    Plourde M, Jew S, Cunnane SC, Jones PJ. Conjugated linoleic acids: why the discrepancy between animal and human studies?. Nutr Rev 2008; 66: 415–421.PubMedCrossRefGoogle Scholar
  4. 4.
    Eulitz K, Yurawecz MP, Sehat N et al. Preparation, separation, and confirmation of the eight geometrical cis/trans conjugated linoleic acid isomers 8,10- through 11,13-18:2. Lipids 1999; 34: 873–877.PubMedCrossRefGoogle Scholar
  5. 5.
    Jung MY, Ha YL. Conjugated linoleic acid isomers in partially hydrogenated soybean oil obtained during nonselective and selective hydrogenation processes. J Agric Food Chem 1999; 47: 704–708.PubMedCrossRefGoogle Scholar
  6. 6.
    Parodi PW. Conjugated Linoleic Acid in Food. Champaign, IL: AOCS Press, 2003.Google Scholar
  7. 7.
    Tricon S, Yaqoob P. Conjugated linoleic acid and human health: a critical evaluation of the evidence. Curr Opin Clin Nutr Metab Care 2006; 9: 105–110.PubMedCrossRefGoogle Scholar
  8. 8.
    Salas-Salvado J, Marquez-Sandoval F, Bullo M. Conjugated linoleic acid intake in humans: a systematic review focusing on its effect on body composition, glucose, and lipid metabolism. Crit Rev Food Sci Nutr 2006; 46: 479–488.PubMedCrossRefGoogle Scholar
  9. 9.
    Koba K, Akahoshi A, Yamasaki M et al. Dietary conjugated linolenic acid in relation to CLA differently modifies body fat mass and serum and liver lipid levels in rats. Lipids 2002; 37: 343–350.PubMedCrossRefGoogle Scholar
  10. 10.
    Ostrowska E, Muralitharan M, Cross RF, Bauman DE, Dunshea FR. Dietary conjugated linoleic acids increase lean tissue and decrease fat deposition in growing pigs. J Nutr 1999; 129: 2037–2042.PubMedGoogle Scholar
  11. 11.
    Szymczyk B, Pisulewski PM, Szczurek W, Hanczakowski P. Effects of conjugated linoleic acid on growth performance, feed conversion efficiency, and subsequent carcass quality in broiler chickens. Br J Nutr 2001; 85: 465–473.PubMedCrossRefGoogle Scholar
  12. 12.
    Whigham LD, Watras AC, Schoeller DA. Efficacy of conjugated linoleic acid for reducing fat mass: a meta-analysis in humans. Am J Clin Nutr 2007; 85: 1203–1211.PubMedGoogle Scholar
  13. 13.
    Pinkoski C, Chilibeck PD, Candow DG et al. The effects of conjugated linoleic acid supplementation during resistance training. Med Sci Sports Exerc 2006; 38: 339–348.PubMedCrossRefGoogle Scholar
  14. 14.
    Mougios V, Matsakas A, Petridou A et al. Effect of supplementation with conjugated linoleic acid on human serum lipids and body fat. J Nutr Biochem 2001; 12: 585–594.PubMedCrossRefGoogle Scholar
  15. 15.
    Smedman A, Vessby B. Conjugated linoleic acid supplementation in humans—metabolic effects. Lipids 2001; 36: 773–781.PubMedCrossRefGoogle Scholar
  16. 16.
    Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid reduces body fat in healthy exercising humans. J Int Med Res 2001; 29: 392–396.PubMedGoogle Scholar
  17. 17.
    Colakoglu S, Colakoglu M, Taneli F, Cetinoz F, Turkmen M. Cumulative effects of conjugated linoleic acid and exercise on endurance development, body composition, serum leptin and insulin levels. J Sports Med Phys Fitness 2006; 46: 570–577.PubMedGoogle Scholar
  18. 18.
    Yalow RS, Berson SA. Dynamics of insulin secretion in early diabetes in humans. Adv Metab Disord 1970; 1(Suppl 1): 95+.PubMedGoogle Scholar
  19. 19.
    Tsochatzis EA, Manolakopoulos S, Papatheodoridis GV, Archimandritis AJ. Insulin resistance and metabolic syndrome in chronic liver diseases: old entities with new implications. Scand J Gastroenterol 2009; 44(1): 6–14.Google Scholar
  20. 20.
    Cowie CC, Rust KF, Ford ES et al. Full accounting of diabetes and pre-diabetes in the US population in 1988–1994 and 2005–2006. Diabetes Care 2009; 32: 287–294.PubMedCrossRefGoogle Scholar
  21. 21.
    Li C, Ford ES, McGuire LC, Mokdad AH, Little RR, Reaven GM. Trends in hyperinsulinemia among nondiabetic adults in the US. Diabetes Care 2006; 29: 2396–2402.PubMedCrossRefGoogle Scholar
  22. 22.
    Smith SC Jr. Multiple risk factors for cardiovascular disease and diabetes mellitus. Am J Med 2007; 120: S3–S11.PubMedCrossRefGoogle Scholar
  23. 23.
    Poirier H, Niot I, Clement L, Guerre-Millo M, Besnard P. Development of conjugated linoleic acid (CLA)-mediated lipoatrophic syndrome in the mouse. Biochimie 2005; 87: 73–79.PubMedCrossRefGoogle Scholar
  24. 24.
    Warren JM, Simon VA, Bartolini G, Erickson KL, Mackey BE, Kelley DS. Trans-10,cis-12 CLA increases liver and decreases adipose tissue lipids in mice: possible roles of specific lipid metabolism genes. Lipids 2003; 38: 497–504.PubMedCrossRefGoogle Scholar
  25. 25.
    Kelley DS, Erickson KL. Modulation of body composition and immune cell functions by conjugated linoleic acid in humans and animal models: benefits vs risks. Lipids 2003; 38: 377–386.PubMedCrossRefGoogle Scholar
  26. 26.
    Noto A, Zahradka P, Ryz NR, Yurkova N, Xie X, Taylor CG. Dietary conjugated linoleic acid preserves pancreatic function and reduces inflammatory markers in obese, insulin-resistant rats. Metabolism 2007; 56: 142–151.PubMedCrossRefGoogle Scholar
  27. 27.
    Wendel AA, Belury MA. Effects of conjugated linoleic acid and troglitazone on lipid accumulation and composition in lean and Zucker diabetic fatty (fa/fa) rats. Lipids 2006; 41: 241–247.PubMedCrossRefGoogle Scholar
  28. 28.
    Nagao K, Inoue N, Wang YM, Yanagita T. Conjugated linoleic acid enhances plasma adiponectin level and alleviates hyperinsulinemia and hypertension in Zucker diabetic fatty (fa/fa) rats. Biochem Biophys Res Commun 2003; 310: 562–566.PubMedCrossRefGoogle Scholar
  29. 29.
    Moloney F, Yeow TP, Mullen A, Nolan JJ, Roche HM. Conjugated linoleic acid supplementation, insulin sensitivity, and lipoprotein metabolism in patients with type 2 diabetes mellitus. Am J Clin Nutr 2004; 80: 887–895.PubMedGoogle Scholar
  30. 30.
    Thrush AB, Chabowski A, Heigenhauser GJ, McBride BW, Or-Rashid M, Dyck DJ. Conjugated linoleic acid increases skeletal muscle ceramide content and decreases insulin sensitivity in overweight, non-diabetic humans. Appl Physiol Nutr Metab 2007; 32: 372–382.PubMedCrossRefGoogle Scholar
  31. 31.
    Tricon S, Burdge GC, Kew S et al. Opposing effects of cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid on blood lipids in healthy humans. Am J Clin Nutr 2004; 80: 614–620.PubMedGoogle Scholar
  32. 32.
    Riserus U, Arner P, Brismar K, Vessby B. Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome. Diabetes Care 2002; 25: 1516–1521.PubMedCrossRefGoogle Scholar
  33. 33.
    Riserus U, Vessby B, Arnlov J, Basu S. Effects of cis-9,trans-11 conjugated linoleic acid supplementation on insulin sensitivity, lipid peroxidation, and proinflammatory markers in obese men. Am J Clin Nutr 2004; 80: 279–283.PubMedGoogle Scholar
  34. 34.
    Riserus U, Vessby B, Arner P, Zethelius B. Supplementation with trans10cis12-conjugated linoleic acid induces hyperproinsulinaemia in obese men: close association with impaired insulin sensitivity. Diabetologia 2004; 47: 1016–1019.PubMedCrossRefGoogle Scholar
  35. 35.
    Gaullier JM, Halse J, Hoye K et al. Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans. J Nutr 2005; 135: 778–784.PubMedGoogle Scholar
  36. 36.
    Tricon S, Burdge GC, Jones EL et al. Effects of dairy products naturally enriched with cis-9,trans-11 conjugated linoleic acid on the blood lipid profile in healthy middle-aged men. Am J Clin Nutr 2006; 83: 744–753.PubMedGoogle Scholar
  37. 37.
    Medina EA, Horn WF, Keim NL et al. Conjugated linoleic acid supplementation in humans: effects on circulating leptin concentrations and appetite. Lipids 2000; 35: 783–788.PubMedCrossRefGoogle Scholar
  38. 38.
    Gaullier JM, Halse J, Hoye K et al. Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. Am J Clin Nutr 2004; 79: 1118–1125.PubMedGoogle Scholar
  39. 39.
    Larsen TM, Toubro S, Gudmundsen O, Astrup A. Conjugated linoleic acid supplementation for 1 year does not prevent weight or body fat regain. Am J Clin Nutr 2006; 83: 606–612.PubMedGoogle Scholar
  40. 40.
    Syvertsen C, Halse J, Hoivik HO et al. The effect of 6 months supplementation with conjugated linoleic acid on insulin resistance in overweight and obese. Int J Obes (Lond) 2007; 31: 1148–1154.CrossRefGoogle Scholar
  41. 41.
    Laso N, Brugue E, Vidal J et al. Effects of milk supplementation with conjugated linoleic acid (isomers cis-9, trans-11 and trans-10, cis-12) on body composition and metabolic syndrome components. Br J Nutr 2007; 98: 860–867.PubMedCrossRefGoogle Scholar
  42. 42.
    Raff M, Tholstrup T, Basu S, Nonboe P, Sorensen MT, Straarup EM. A diet rich in conjugated linoleic acid and butter increases lipid peroxidation but does not affect atherosclerotic, inflammatory, or diabetic risk markers in healthy young men. J Nutr 2008; 138: 509–514.PubMedGoogle Scholar
  43. 43.
    Eyjolfson V, Spriet LL, Dyck DJ. Conjugated linoleic acid improves insulin sensitivity in young, sedentary humans. Med Sci Sports Exerc 2004; 36: 814–820.PubMedGoogle Scholar
  44. 44.
    Lambert EV, Goedecke JH, Bluett K et al. Conjugated linoleic acid versus high-oleic acid sunflower oil: effects on energy metabolism, glucose tolerance, blood lipids, appetite and body composition in regularly exercising individuals. Br J Nutr 2007; 97: 1001–1011.PubMedCrossRefGoogle Scholar
  45. 45.
    Erickson SK. Nonalcoholic fatty liver disease (NAFLD). J Lipid Res 2009 Apr; 50(Suppl): S412–6.Google Scholar
  46. 46.
    Erickson SK. Nonalcoholic fatty liver disease. J Lipid Res 2009; 50(Suppl): S412–S416.PubMedCrossRefGoogle Scholar
  47. 47.
    Kelley DS, Bartolini GL, Warren JM, Simon VA, Mackey BE, Erickson KL. Contrasting effects of t10, c12- and c9,t11-conjugated linoleic acid isomers on the fatty acid profiles of mouse liver lipids. Lipids 2004; 39: 135–141.Google Scholar
  48. 48.
    Ramos R, Mascarenhas J, Duarte P, Vicente C, Casteleiro C. Conjugated linoleic acid-induced toxic hepatitis: first case report. Dig Dis Sci 2008; 54(5): 1141–1143.PubMedCrossRefGoogle Scholar
  49. 49.
    Iwata T, Kamegai T, Yamauchi-Sato Y et al. Safety of dietary conjugated linoleic acid (CLA) in a 12-weeks trial in healthy overweight Japanese male volunteers. J Oleo Sci 2007; 56: 517–525.PubMedCrossRefGoogle Scholar
  50. 50.
    Mariotti F, Hermier D, Sarrat C et al. Rapeseed protein inhibits the initiation of insulin resistance by a high-saturated fat, high-sucrose diet in rats. Br J Nutr 2008; 100: 984–991.PubMedCrossRefGoogle Scholar
  51. 51.
    Ascencio C, Torres N, Isoard-Acosta F, Gomez-Perez FJ, Hernandez-Pando R, Tovar AR. Soy protein affects serum insulin and hepatic SREBP-1 mRNA and reduces fatty liver in rats. J Nutr 2004; 134: 522–529.PubMedGoogle Scholar
  52. 52.
    Badger TM, Ronis MJ, Wolff G et al. Soy protein isolate reduces hepatosteatosis in yellow Avy/a mice without altering coat color phenotype. Exp Biol Med (Maywood) 2008; 233: 1242–1254.CrossRefGoogle Scholar
  53. 53.
    Shukla A, Brandsch C, Bettzieche A, Hirche F, Stangl GI, Eder K. Isoflavone-poor soy protein alters the lipid metabolism of rats by SREBP-mediated down-regulation of hepatic genes. J Nutr Biochem 2007; 18: 313–321.PubMedCrossRefGoogle Scholar
  54. 54.
    Gudbrandsen OA, Wergedahl H, Liaset B, Espe M, Berge RK. Dietary proteins with high isoflavone content or low methionine–glycine and lysine–arginine ratios are hypocholesterolaemic and lower the plasma homocysteine level in male Zucker fa/fa rats. Br J Nutr 2005; 94: 321–330.PubMedCrossRefGoogle Scholar
  55. 55.
    Araya J, Rodrigo R, Videla LA et al. Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond) 2004; 106: 635–643.CrossRefGoogle Scholar
  56. 56.
    El-Badry AM, Graf R, Clavien PA. Omega 3—Omega 6: What is right for the liver? J Hepatol 2007; 47: 718–725.PubMedCrossRefGoogle Scholar
  57. 57.
    Kelley DS, Bartolini GL, Newman JW, Vemuri M, Mackey BE. Fatty acid composition of liver, adipose tissue, spleen, and heart of mice fed diets containing t10, c12-, and c9, t11-conjugated linoleic acid. Prostaglandins Leukot Essent Fatty Acids 2006; 74: 331–338.PubMedCrossRefGoogle Scholar
  58. 58.
    Clement L, Poirier H, Niot I et al. Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse. J Lipid Res 2002; 43: 1400–1409.PubMedCrossRefGoogle Scholar
  59. 59.
    Javadi M, Beynen AC, Hovenier R et al. Prolonged feeding of mice with conjugated linoleic acid increases hepatic fatty acid synthesis relative to oxidation. J Nutr Biochem 2004; 15: 680–687.PubMedCrossRefGoogle Scholar
  60. 60.
    Roche HM, Noone E, Sewter C et al. Isomer-dependent metabolic effects of conjugated linoleic acid: insights from molecular markers sterol regulatory element-binding protein-1c and LXRalpha. Diabetes 2002; 51: 2037–2044.PubMedCrossRefGoogle Scholar
  61. 61.
    Takahashi Y, Kushiro M, Shinohara K, Ide T. Activity and mRNA levels of enzymes involved in hepatic fatty acid synthesis and oxidation in mice fed conjugated linoleic acid. Biochim Biophys Acta 2003; 1631: 265–273.PubMedCrossRefGoogle Scholar
  62. 62.
    Tsuboyama-Kasaoka N, Takahashi M, Tanemura K et al. Conjugated linoleic acid supplementation reduces adipose tissue by apoptosis and develops lipodystrophy in mice. Diabetes 2000; 49: 1534–1542.PubMedCrossRefGoogle Scholar
  63. 63.
    Winzell MS, Pacini G, Ahren B. Insulin secretion after dietary supplementation with conjugated linoleic acids and n-3 polyunsaturated fatty acids in normal and insulin-resistant mice. Am J Physiol Endocrinol Metab 2006; 290: E347–E354.PubMedCrossRefGoogle Scholar
  64. 64.
    Rasooly R, Kelley DS, Greg J, Mackey BE. Dietary trans 10, cis 12-conjugated linoleic acid reduces the expression of fatty acid oxidation and drug detoxification enzymes in mouse liver. Br J Nutr 2007; 97: 58–66.PubMedCrossRefGoogle Scholar
  65. 65.
    Capanni M, Calella F, Biagini MR et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 2006; 23: 1143–1151.PubMedCrossRefGoogle Scholar
  66. 66.
    Delarue J, LeFoll C, Corporeau C, Lucas DN-. n-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? Reprod Nutr Dev 2004; 44: 289–299.PubMedCrossRefGoogle Scholar
  67. 67.
    Flachs P, Mohamed-Ali V, Horakova O et al. Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet. Diabetologia 2006; 49: 394–397.PubMedCrossRefGoogle Scholar
  68. 68.
    Le Foll C, Corporeau C, Le Guen V, Gouygou JP, Berge JP, Delarue J. Long-chain n-3 polyunsaturated fatty acids dissociate phosphorylation of Akt from phosphatidylinositol 3'-kinase activity in rats. Am J Physiol Endocrinol Metab 2007; 292: E1223–E1230.PubMedCrossRefGoogle Scholar
  69. 69.
    Ghafoorunissa IA, Rajkumar L, Acharya V. Dietary (n-3) long chain polyunsaturated fatty acids prevent sucrose-induced insulin resistance in rats. J Nutr 2005; 135: 2634–2638.PubMedGoogle Scholar
  70. 70.
    Rossi AS, Lombardo YB, Lacorte JM et al. Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats. Am J Physiol Regul Integr Comp Physiol 2005; 289: R486–R494.PubMedCrossRefGoogle Scholar
  71. 71.
    Alwayn IP, Gura K, Nose V et al. Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatr Res 2005; 57: 445–452.PubMedCrossRefGoogle Scholar
  72. 72.
    Gonzalez-Periz A, Horrillo R, Ferre N et al. Obesity-induced insulin resistance and hepatic steatosis are alleviated by {omega}-3 fatty acids: a role for resolvins and protectins. FASEBb J 2009; 23: 1946–1957.CrossRefGoogle Scholar
  73. 73.
    Ide T. Interaction of fish oil and conjugated linoleic acid in affecting hepatic activity of lipogenic enzymes and gene expression in liver and adipose tissue. Diabetes 2005; 54: 412–423.PubMedCrossRefGoogle Scholar
  74. 74.
    Vemuri M, Kelley DS, Mackey BE, Rasooly R, Bartolini G. Docosahexaenoic acid (DHA) but not eicosapentaenoic acid (EPA) prevents trans-10, cis-12 conjugated linoleic acid (CLA)-induced insulin resistance in mice. Metabol Syndr Relat Dis 2007; 5: 315–322.CrossRefGoogle Scholar
  75. 75.
    Yanagita T, Wang YM, Nagao K, Ujino Y, Inoue N. Conjugated linoleic acid-induced fatty liver can be attenuated by combination with docosahexaenoic acid in C57BL/6 N mice. J Agric Food Chem 2005; 53: 9629–9633.PubMedCrossRefGoogle Scholar
  76. 76.
    Murase T, Aoki M, Tokimitsu I. Supplementation with alpha-linolenic acid-rich diacylglycerol suppresses fatty liver formation accompanied by an up-regulation of beta-oxidation in Zucker fatty rats. Biochim Biophys Acta 2005; 1733: 224–231.PubMedCrossRefGoogle Scholar
  77. 77.
    Mustad VA, Demichele S, Huang YS et al. Differential effects of n-3 polyunsaturated fatty acids on metabolic control and vascular reactivity in the type 2 diabetic ob/ob mouse. Metabolism 2006; 55: 1365–1374.PubMedCrossRefGoogle Scholar
  78. 78.
    Kelley DS, Vemuri M, Adkins Y, Gill SH, Fedor D, Mackey BE. Flaxseed oil prevents trans-10, cis-12-conjugated linoleic acid-induced insulin resistance in mice. Br J Nutr 2009; 101: 701–708.PubMedCrossRefGoogle Scholar
  79. 79.
    Chung S, Brown JM, Provo JN, Hopkins R, McIntosh MK. Conjugated linoleic acid promotes human adipocyte insulin resistance through NFkappaB-dependent cytokine production. J Biol Chem 2005; 280: 38445–38456.PubMedCrossRefGoogle Scholar
  80. 80.
    Poirier H, Rouault C, Clement L et al. Hyperinsulinaemia triggered by dietary conjugated linoleic acid is associated with a decrease in leptin and adiponectin plasma levels and pancreatic beta cell hyperplasia in the mouse. Diabetologia 2005; 48: 1059–1065.PubMedCrossRefGoogle Scholar
  81. 81.
    Purushotham A, Wendel AA, Liu LF, Belury MA. Maintenance of adiponectin attenuates insulin resistance induced by dietary conjugated linoleic acid in mice. J Lipid Res 2007; 48: 444–452.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Nutrition, Western Human Nutrition Research Center, ARS, USDAUniversity of CaliforniaDavisUSA
  2. 2.Western Human Nutrition Research Center, ARS, USDA, Department of NutritionUniversity of CaliforniaDavisUSA

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