Journal of Physiology and Biochemistry

, Volume 69, Issue 3, pp 595–600 | Cite as

Lipoic acid inhibits adiponectin production in 3T3-L1 adipocytes

  • Pedro L. Prieto-Hontoria
  • Marta Fernández-Galilea
  • Patricia Pérez-Matute
  • J. Alfredo Martínez
  • María J. Moreno-Aliaga
Original Paper


Lipoic acid (LA) is a naturally occurring compound with antioxidant properties. Recent attention has been focused on the potential beneficial effects of LA on obesity and related metabolic disorders. Dietary supplementation with LA prevents insulin resistance and upregulates adiponectin, an insulin-sensitizing adipokine, in obese rodents. The aim of this study was to investigate the direct effects of LA on adiponectin production in cultured adipocytes, as well as the potential signaling pathways involved. For this purpose, fully differentiated 3T3-L1 adipocytes were treated with LA (1–500 μM) during 24 h. The amount of adiponectin secreted to media was detected by ELISA, while adiponectin mRNA expression was determined by RT-PCR. Treatment with LA induced a dose-dependent inhibition on adiponectin gene expression and protein secretion. Pretreatment with the PI3K inhibitor LY294002 inhibited adiponectin secretion and mRNA levels, and significantly potentiated the inhibitory effect of LA on adiponectin secretion. The AMPK activator AICAR also reduced adiponectin production, but surprisingly, it was able to reverse the LA-induced inhibition of adiponectin. The JNK inhibitor SP600125 and the MAPK inhibitor PD98059 did not modify the inhibitory effect of LA on adiponectin. In conclusion, our results revealed that LA reduces adiponectin secretion in 3T3-L1 adipocytes, which contrasts with the stimulation of adiponectin described after in vivo supplementation with LA, suggesting that an indirect mechanism or some in vivo metabolic processing is involved.


Lipoic acid Obesity Adiponectin Adipocytes 



This work has been supported by the Ministry of Science and Innovation of the Government of Spain (AGL 2009-10873/ALI and AGL 2006-04716/ALI) and by Línea Especial: “Nutrición, Obesidad y Salud” (University of Navarra). PL Prieto-Hontoria was supported by a research grant by Danone Institute, Spain. CTP, CIBERobn, and RETICS Network are gratefully acknowledged.

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Barth N, Langmann T, Scholmerich J, Schmitz G, Schaffler A (2002) Identification of regulatory elements in the human adipose most abundant gene transcript-1 (Apm-1) promoter: role of Sp1/Sp3 and TNF-alpha as regulatory pathways. Diabetologia 45(10):1425–1433PubMedGoogle Scholar
  2. 2.
    Blumer RM, van Roomen CP, Meijer AJ, Houben-Weerts JH, Sauerwein HP, Dubbelhuis PF (2008) Regulation of adiponectin secretion by insulin and amino acids in 3T3-L1 adipocytes. Metabolism 57(12):1655–1662PubMedCrossRefGoogle Scholar
  3. 3.
    Carbonelli MG, Di Renzo L, Bigioni M, Di Daniele N, De Lorenzo A, Fusco MA (2010) Alpha-lipoic acid supplementation: a tool for obesity therapy? Curr Pharm Des 16(7):840–846PubMedCrossRefGoogle Scholar
  4. 4.
    Cho KJ, Moon HE, Moini H, Packer L, Yoon DY, Chung AS (2003) Alpha-lipoic acid inhibits adipocyte differentiation by regulating pro-adipogenic transcription factors via mitogen-activated protein kinase pathways. J Biol Chem 278(37):34823–34833PubMedCrossRefGoogle Scholar
  5. 5.
    Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R (2002) Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 290(3):1084–1089PubMedCrossRefGoogle Scholar
  6. 6.
    Fernandez-Galilea M, Perez-Matute P, Prieto-Hontoria P, Martinez JA, Moreno-Aliaga MJ (2011) Effects of lipoic acid on apelin in 3T3-L1 adipocytes and in high-fat fed rats. J Physiol Biochem 67(3):479–486PubMedCrossRefGoogle Scholar
  7. 7.
    Fernandez-Galilea M, Perez-Matute P, Prieto-Hontoria PL, Martinez JA, Moreno-Aliaga MJ (2012) Effects of lipoic acid on lipolysis in 3T3-L1 adipocytes. J Lipid Res 53(11):2296–2306PubMedCrossRefGoogle Scholar
  8. 8.
    Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, Singh GM, Gutierrez HR, Lu Y, Bahalim AN, Farzadfar F, Riley LM, Ezzati M (2011) National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 377(9765):557–567PubMedCrossRefGoogle Scholar
  9. 9.
    Garcia-Diaz DF, Campion J, Milagro FI, Boque N, Moreno-Aliaga MJ, Martinez JA (2010) Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes. J Mol Endocrinol 45(1):33–43PubMedCrossRefGoogle Scholar
  10. 10.
    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444(7121):860–867PubMedCrossRefGoogle Scholar
  11. 11.
    Huypens P, Quartier E, Pipeleers D, Van de Casteele M (2005) Metformin reduces adiponectin protein expression and release in 3T3-L1 adipocytes involving activation of AMP activated protein kinase. Eur J Pharmacol 518(2–3):90–95PubMedCrossRefGoogle Scholar
  12. 12.
    Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, Lee IK, Viollet B, Youn JH, Lee HK, Lee KU (2004) Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic amp-activated protein kinase. Nat Med 10(7):727–733PubMedCrossRefGoogle Scholar
  13. 13.
    Koh EH, Lee WJ, Lee SA, Kim EH, Cho EH, Jeong E, Kim DW, Kim MS, Park JY, Park KG, Lee HJ, Lee IK, Lim S, Jang HC, Lee KH, Lee KU (2011) Effects of alpha-lipoic acid on body weight in obese subjects. Am J Med 124(1):e81–e88CrossRefGoogle Scholar
  14. 14.
    Landrier JF, Gouranton E, El Yazidi C, Malezet C, Balaguer P, Borel P, Amiot MJ (2009) Adiponectin expression is induced by vitamin E via a peroxisome proliferator-activated receptor gamma-dependent mechanism. Endocrinology 150(12):5318–5325PubMedCrossRefGoogle Scholar
  15. 15.
    Lihn AS, Jessen N, Pedersen SB, Lund S, Richelsen B (2004) Aicar stimulates adiponectin and inhibits cytokines in adipose tissue. Biochem Biophys Res Commun 316(3):853–858PubMedCrossRefGoogle Scholar
  16. 16.
    Liu M, Liu F (2010) Transcriptional and post-translational regulation of adiponectin. Biochem J 425(1):41–52CrossRefGoogle Scholar
  17. 17.
    Moini H, Tirosh O, Park YC, Cho KJ, Packer L (2002) R-alpha-lipoic acid action on cell redox status, the insulin receptor, and glucose uptake in 3T3-L1 adipocytes. Arch Biochem Biophys 397(2):384–391PubMedCrossRefGoogle Scholar
  18. 18.
    Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11(2):85–97PubMedCrossRefGoogle Scholar
  19. 19.
    Pereira RI, Draznin B (2005) Inhibition of the phosphatidylinositol 3′-kinase signaling pathway leads to decreased insulin-stimulated adiponectin secretion from 3T3-L1 adipocytes. Metabolism 54(12):1636–1643PubMedCrossRefGoogle Scholar
  20. 20.
    Prieto-Hontoria PL, Perez-Matute P, Fernandez-Galilea M, Barber A, Martinez JA, Moreno-Aliaga MJ (2009) Lipoic acid prevents body weight gain induced by a high fat diet in rats: effects on intestinal sugar transport. J Physiol Biochem 65(1):43–50PubMedCrossRefGoogle Scholar
  21. 21.
    Prieto-Hontoria PL, Perez-Matute P, Fernandez-Galilea M, Martinez JA, Moreno-Aliaga MJ (2011) Lipoic acid inhibits leptin secretion and Sp1 activity in adipocytes. Mol Nutr Food Res 55(7):1059–1069PubMedCrossRefGoogle Scholar
  22. 22.
    Prieto-Hontoria PL, Perez-Matute P, Fernandez-Galilea M, Martinez JA, Moreno-Aliaga MJ (2013) Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr (in press)Google Scholar
  23. 23.
    Qin ZY, Zhang M, Guo XR, Wang YM, Zhu GZ, Ni YH, Zhao YP, Qiu J, Kou CZ, Qin R, Cao XG (2012) Alpha-lipoic acid ameliorates impaired glucose uptake in LYRM1 overexpressing 3T3-L1 adipocytes through the IRS-1/AKT signaling pathway. J Bioenerg Biomembr 44(5):579–586PubMedCrossRefGoogle Scholar
  24. 24.
    Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM (2009) Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta 1790(10):1149–1160PubMedCrossRefGoogle Scholar
  25. 25.
    Shen W, Hao J, Feng Z, Tian C, Chen W, Packer L, Shi X, Zang W, Liu J (2011) Lipoamide or lipoic acid stimulates mitochondrial biogenesis in 3T3-L1 adipocytes via the endothelial NO synthase-cGMP-protein kinase G signalling pathway. Br J Pharmacol 162(5):1213–1224PubMedCrossRefGoogle Scholar
  26. 26.
    Shi DY, Liu HL, Stern JS, Yu PZ, Liu SL (2008) Alpha-lipoic acid induces apoptosis in hepatoma cells via the PTEN/AKT pathway. FEBS Lett 582(12):1667–1671PubMedCrossRefGoogle Scholar
  27. 27.
    Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116(7):1793–1801PubMedCrossRefGoogle Scholar
  28. 28.
    Tishinsky JM, Ma DW, Robinson LE (2011) Eicosapentaenoic acid and rosiglitazone increase adiponectin in an additive and PPARγ-dependent manner in human adipocytes. Obesity (Silver Spring) 19(2):262–268CrossRefGoogle Scholar
  29. 29.
    Turer AT, Scherer PE (2012) Adiponectin: mechanistic insights and clinical implications. Diabetologia 55(9):2319–2326PubMedCrossRefGoogle Scholar
  30. 30.
    Vincent HK, Innes KE, Vincent KR (2007) Oxidative stress and potential interventions to reduce oxidative stress in overweight and obesity. Diabetes Obes Metab 9(6):813–839PubMedCrossRefGoogle Scholar
  31. 31.
    Wang Y, Lam KS, Yau MH, Xu A (2008) Post-translational modifications of adiponectin: mechanisms and functional implications. Biochem J 409(3):623–633PubMedCrossRefGoogle Scholar
  32. 32.
    Wang YM, Lin XF, Shi CM, Lu L, Qin ZY, Zhu GZ, Cao XG, Ji CB, Qiu J, Guo XR (2012) Alpha-lipoic acid protects 3T3-L1 adipocytes from NYGGF4 (PID1) overexpression-induced insulin resistance through increasing phosphorylation of IRS-1 and AKT. J Bioenerg Biomembr 44(3):357–363PubMedCrossRefGoogle Scholar
  33. 33.
    Wang A, Liu M, Liu X, Dong LQ, Glickman RD, Slaga TJ, Zhou Z, Liu F (2011) Up-regulation of adiponectin by resveratrol: the essential roles of the AKT/FOXO1 and AMP-activated protein kinase signaling pathways and DSBA-l. J Biol Chem 286(1):60–66PubMedCrossRefGoogle Scholar
  34. 34.
    Wu X, Motoshima H, Mahadev K, Stalker TJ, Scalia R, Goldstein BJ (2003) Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes 52(6):1355–1363PubMedCrossRefGoogle Scholar
  35. 35.
    Yamada M, Kaibori M, Tanaka H, Habara K, Hijikawa T, Tanaka Y, Oishi M, Okumura T, Nishizawa M, Kwon AH (2012) Alpha-lipoic acid prevents the induction of iNOS gene expression through destabilization of its mrna in proinflammatory cytokine-stimulated hepatocytes. Dig Dis Sci 57(4):943–951PubMedCrossRefGoogle Scholar
  36. 36.
    Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating amp-activated protein kinase. Nat Med 8(11):1288–1295PubMedCrossRefGoogle Scholar
  37. 37.
    Yu S, Zhang Y, Li MZ, Xu H, Wang Q, Song J, Lin P, Zhang L, Liu Q, Huang QX, Wang K, Hou WK (2012) Chemerin and apelin are positively correlated with inflammation in obese type 2 diabetic patients. Chin Med J (Engl) 125(19):3440–3444Google Scholar
  38. 38.
    Zhang Y, Han P, Wu N, He B, Lu Y, Li S, Liu Y, Zhao S, Liu L, Li Y (2011) Amelioration of lipid abnormalities by alpha-lipoic acid through antioxidative and anti-inflammatory effects. Obesity (Silver Spring) 19(8):1647–1653CrossRefGoogle Scholar
  39. 39.
    Ziemke F, Mantzoros CS (2010) Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr 91(1):258S–261SPubMedCrossRefGoogle Scholar

Copyright information

© University of Navarra 2013

Authors and Affiliations

  • Pedro L. Prieto-Hontoria
    • 1
  • Marta Fernández-Galilea
    • 1
  • Patricia Pérez-Matute
    • 1
    • 2
  • J. Alfredo Martínez
    • 1
  • María J. Moreno-Aliaga
    • 1
  1. 1.Department of Nutrition, Food Science and PhysiologyUniversity of NavarraPamplonaSpain
  2. 2.HIV and Associated Metabolic Alterations Unit, Infectious Diseases AreaCenter for Biomedical Research of La Rioja (CIBIR)LogroñoSpain

Personalised recommendations