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Horm Metab Res 2007; 39(3): 186-191
DOI: 10.1055/s-2007-970416
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Conjugated Linoleic Acids Promote Human Fat Cell Apoptosis

P. Fischer-Posovszky 1 , V. Kukulus 1 , M. A. Zulet 2 , K. M. Debatin 1 , M. Wabitsch 1
  • 1Department of Pediatrics and Adolescent Medicine, University of Ulm, 89075 Ulm, Germany
  • 2Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain
Further Information

Publication History

received 22. 6. 2006

accepted 6. 11. 2006

Publication Date:
20 March 2007 (online)

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Abstract

Conjugated linoleic acids (CLAs) are conjugated dienoic isomers of linoleic acid. Some isomers have been shown to reduce fat mass in animal and cell culture models. However, controversial results were obtained in studies of supplementation of CLAs in human subjects. In order to get more insights into the direct effects of CLAs on human fat cells, we have studied the influence of cis-9,trans-11 CLA and trans-10,cis-12 CLA on the biology of human SGBS preadipocytes and adipocytes. Both CLA isomers equally inhibited the proliferation of preadipocytes in a dose-dependent manner. Continuous treatment with 1-10 μM trans-10,cis-12 CLA, and to a weaker extent cis-9,trans-11 CLA, inhibited accumulation of lipids during adipogenic differentiation. Treatment with higher doses of CLA induced apoptosis in preadipocytes, in differentiating cells, and adipocytes. The trans-10,cis-12 isomer had a higher apoptotic potency in adipocytes than cis-9,trans-11 CLA. Taken together, the treatment of human preadipocytes and adipocytes with physiological relevant concentrations of CLAs resulted in an impairment of proliferation and differentiation and induction of apoptosis. The trans-10,cis-12 isomer was more potent than the cis-9,trans-11 isomer. Further clinical studies are needed to evaluate the effects of CLAs on human fat mass and metabolism in vivo.

Key words

CLA - preadipocyte - adipocyte - adipose tissue - obesity - apoptosis

References

  • 1 Pariza MW, Park Y, Cook ME. The biologically active isomers of conjugated linoleic acid.  Prog Lipid Res. 2001;  40 283-298
    PubMedSearch in Google Scholar
  • 2 Brown J, McIntosh MK. Conjugated linoleic acid in humans: regulation of adiposity and insulin sensitivity.  J Nutr. 2003;  133 3041-3046
    PubMedSearch in Google Scholar
  • 3 Belury MA. Inhibition of carcinogenesis by conjugated linoleic acid: potential mechanisms of action.  J Nutr. 2002;  132 2995-2998
    PubMedSearch in Google Scholar
  • 4 House RL, Cassady JP, Eisen EJ, McIntosh MK, Odle J. Conjugated linoleic acid evokes de-lipidation through the regulation of genes controlling lipid metabolism in adipose and liver tissue.  Obes Rev. 2005;  6 247-258
    CrossrefPubMedSearch in Google Scholar
  • 5 Tricon S, Burdge GC, Williams CM, Calder PC, Yaqoob P. The effects of conjugated linoleic acid on human health-related outcomes.  Proc Nutr Soc. 2005;  64 171-182
    CrossrefPubMedSearch in Google Scholar
  • 6 Larsen TM, Toubro S, Astrup A. Efficacy and safety of dietary supplements containing CLA for the treatment of obesity: evidence from animal and human studies.  J Lipid Res. 2003;  44 2234-2241
    PubMedSearch in Google Scholar
  • 7 Feve B. Adipogenesis: cellular and molecular aspects.  Best Pract Res Clin Endocrinol Metab. 2005;  19 483-499
    CrossrefPubMedSearch in Google Scholar
  • 8 Fischer-Posovszky P, Tornqvist H, Debatin KM, Wabitsch M. Inhibition of death-receptor mediated apoptosis in human adipocytes by the insulin-like growth factor I (IGF-I)/IGF-I receptor autocrine circuit.  Endocrinology. 2004;  145 1849-1859
    CrossrefPubMedSearch in Google Scholar
  • 9 Brown JM, Boysen MS, Jensen SS, Morrison RF, Storkson J, Lea-Currie R, Pariza M, Mandrup S, McIntosh MK. Isomer-specific regulation of metabolism and PPARgamma signaling by CLA in human preadipocytes.  J Lipid Res. 2003;  44 1287-1300
    PubMedSearch in Google Scholar
  • 10 Granlund L, Juvet LK, Pedersen JI, Nebb HI. Trans-10,cis-12-conjugated linoleic acid prevents triacylglycerol accumulation in adipocytes by acting as a PPARgamma modulator.  J Lipid Res. 2003;  44 1441-1452
    PubMedSearch in Google Scholar
  • 11 Granlund L, Pedersen JI, Nebb HI. Impaired lipid accumulation by trans-10,cis-12 CLA during adipocyte differentiation is dependent on timing and length of treatment.  Biochim Biophys Acta. 2005;  1687 11-22
    PubMedSearch in Google Scholar
  • 12 Brown JM, Boysen MS, Chung S, Fabiyi O, Morrison RF, Mandrup S, McIntosh MK. Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines.  J Biol Chem. 2004;  279 26735-26747
    CrossrefPubMedSearch in Google Scholar
  • 13 Hung S, Brown JM, Sandberg MB, McIntosh M. Trans-10,cis-12 CLA increases adipocyte lipolysis and alters lipid droplet-associated proteins: role of mTOR and ERK signaling.  J Lipid Res. 2005;  46 885-895
    PubMedSearch in Google Scholar
  • 14 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
    CrossrefPubMedSearch in Google Scholar
  • 15 Poirier H, Shapiro JS, Kim RJ, Lazar MA. Nutritional supplementation with trans-10,cis-12-conjugated linoleic acid induces inflammation of white adipose tissue.  Diabetes. 2006;  55 1634-1641
    CrossrefPubMedSearch in Google Scholar
  • 16 Bassaganya-Riera J, Hontecillas R, Beitz DC. Colonic anti-inflammatory mechanisms of conjugated linoleic acid.  Clin Nutr. 2002;  21 451-459
    CrossrefPubMedSearch in Google Scholar
  • 17 Toomey S, Roche H, Fitzgerald D, Belton O. Regression of pre-established atherosclerosis in the apoE-/- mouse by conjugated linoleic acid.  Biochem Soc Trans. 2003;  31 1075-1079
    PubMedSearch in Google Scholar
  • 18 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
    PubMedSearch in Google Scholar
  • 19 Basu S, Smedman A, Vessby B. Conjugated linoleic acid induces lipid peroxidation in humans.  FEBS Lett. 2000;  468 33-36
    CrossrefPubMedSearch in Google Scholar
  • 20 Basu S, Riserus U, Turpeinen A, Vessby B. Conjugated linoleic acid induces lipid peroxidation in men with abdominal obesity.  Clin Sci (Lond). 2000;  99 511-516
    PubMedSearch in Google Scholar
  • 21 Blankson H, Stakkestad JA, Fagertun H, Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid reduces body fat mass in overweight and obese humans.  J Nutr. 2000;  130 2943-2948
    PubMedSearch in Google Scholar
  • 22 Wabitsch M, Brenner RE, Melzner I, Braun M, Möller P, Heinze E, Debatin KM, Hauner H. Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation.  Int J Obes Relat Metab Disord. 2001;  25 8-15
    CrossrefPubMedSearch in Google Scholar
  • 23 Janderova L, McNeil M, Murrell AN, Mynatt RL, Smith SR. Human mesenchymal stem cells as an in vitro model for human adipogenesis.  Obes Res. 2003;  11 65-74
    PubMedSearch in Google Scholar
  • 24 Terpstra AH. Effect of conjugated linoleic acid on body composition and plasma lipids in humans: an overview of the literature.  Am J Clin Nutr. 2004;  79 352-361
    PubMedSearch in Google Scholar
  • 25 Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid reduces body fat in healthy exercising humans.  J Int Med Res. 2001;  29 392-396
    PubMedSearch in Google Scholar
  • 26 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
    PubMedSearch in Google Scholar
  • 27 Smedman A, Vessby B. Conjugated linoleic acid supplementation in humans-metabolic effects.  Lipids. 2001;  36 773-781
    PubMedSearch in Google Scholar
  • 28 Satory DL, Smith SB. Conjugated linoleic acid inhibits proliferation but stimulates lipid filling of murine 3T3-L1 preadipocytes.  J Nutr. 1999;  129 92-97
    PubMedSearch in Google Scholar
  • 29 Evans M, Geigerman C, Cook J, Curtis L, Kuebler B, McIntosh M. Conjugated linoleic acid suppresses triglyceride accumulation and induces apoptosis in 3T3-L1 preadipocytes.  Lipids. 2000;  35 899-910
    CrossrefPubMedSearch in Google Scholar
  • 30 Brandebourg TD, Hu CY. Isomer-specific regulation of differentiating pig preadipocytes by conjugated linoleic acids.  J Anim Sci. 2005;  83 2096-2105
    PubMedSearch in Google Scholar
  • 31 Brown JM, Halvorsen YD, Lea-Currie YR, Geigerman C, McIntosh M. Trans-10,cis-12, but not cis-9,trans-11, conjugated linoleic acid attenuates lipogenesis in primary cultures of stromal vascular cells from human adipose tissue.  J Nutr. 2001;  131 2316-2321
    PubMedSearch in Google Scholar
  • 32 Brown M, Evans M, McIntosh M. Linoleic acid partially restores the triglyceride content of conjugated linoleic acid-treated cultures of 3T3-L1 preadipocytes.  J Nutr Biochem. 2001;  12 381-387
    PubMedSearch in Google Scholar
  • 33 Hauner H, Entenmann G, Wabitsch M, Gaillard D, Ailhaud G, Negrel R, Pfeiffer EF. Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium.  J Clin Invest. 1989;  84 1663-1670
    PubMedSearch in Google Scholar
  • 34 Porras A, Alvarez AM, Valladares A, Benito M. TNF-alpha induces apoptosis in rat fetal brown adipocytes in primary culture.  FEBS Lett. 1997;  416 324-328
    CrossrefPubMedSearch in Google Scholar
  • 35 Magun R, Boone DL, Tsang BK, Sorisky A. The effect of adipocyte differentiation on the capacity of 3T3-L1 cells to undergo apoptosis in response to growth factor deprivation.  Int J Obes Relat Metab Disord. 1998;  22 567-571
    CrossrefPubMedSearch in Google Scholar
  • 36 Hargrave KM, Li C, Meyer BJ, Kachman SD, Hartzell DL, Della-Fera MA, Miner JL, Baile CA. Adipose depletion and apoptosis induced by trans-10,cis-12 conjugated linoleic Acid in mice.  Obes Res. 2002;  10 1284-1290
    PubMedSearch in Google Scholar
  • 37 Masso-Welch PA, Zangani D, Ip C, Vaughan MM, Shoemaker SF, McGee SO, Ip MM. Isomers of conjugated linoleic acid differ in their effects on angiogenesis and survival of mouse mammary adipose vasculature.  J Nutr. 2004;  134 299-307
    PubMedSearch in Google Scholar
  • 38 Tang DG, La E, Kern J, Kehrer J. Fatty acid oxidation and signaling in apoptosis.  Biol Chem. 2002;  383 425-442
    CrossrefPubMedSearch in Google Scholar
  • 39 Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, Portocarrero CP, Peck LW, Nickel KP, Belury MA. Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat.  Biochem Biophys Res Commun. 1998;  244 678-682
    CrossrefPubMedSearch in Google Scholar

Correspondence

M. Wabitsch

Pediatric Endocrinology · Department of Pediatrics and Adolescent Medicine · University of Ulm

Eythstr 24

89075 Ulm

Germany

Phone: +49/731/5002 77 15

Fax: +49/731/5002 67 14

Email: martin.wabitsch@uniklinik-ulm.de