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Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats

Abstract

Background

Lipoic acid (LA) is an antioxidant with antiobesity and antidiabetic properties. Adiponectin is an adipokine with potent anti-inflammatory and insulin-sensitizing properties. AMP-activated protein kinase (AMPK) is a key enzyme involved in cellular energy homeostasis. Activation of AMPK has been considered as a target to reverse the metabolic abnormalities associated with obesity and type 2 diabetes.

Aim of the study

The aim of this study was to determine the effects of LA on AMPK phosphorylation and adiponectin production in adipose tissue of low-fat (control diet) and high-fat diet-fed rats.

Results

Dietary supplementation with LA reduced body weight and adiposity in control and high-fat-fed rats. LA also reduced basal hyperinsulinemia as well as the homeostasis model assessment (HOMA) levels, an index of insulin resistance, in high-fat-fed rats, which was in part independent of their food intake lowering actions. Furthermore, AMPK phosphorylation was increased in white adipose tissue (WAT) from LA-treated rats as compared with pair-fed animals. Dietary supplementation with LA also upregulated adiponectin gene expression in WAT, while a negative correlation between adiposity-corrected adiponectin levels and HOMA index was found. Our present data suggest that the ability of LA supplementation to prevent insulin resistance in high-fat diet-fed rats might be related in part to the stimulation of AMPK and adiponectin in WAT.

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Abbreviations

AMPK:

AMP-activated protein kinase

HOMA:

Homeostasis model assessment

LA:

Lipoic acid

LASY:

Lipoic acid synthase

TZDs:

Thiazolidinediones

WAT:

White adipose tissue

BAT:

Brown adipose tissue

References

  1. Marti A, Martinez-Gonzalez MA, Martinez JA (2008) Interaction between genes and lifestyle factors on obesity. Proc Nutr Soc 67:1–8

    Article  CAS  Google Scholar 

  2. Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11:85–97

    Article  CAS  Google Scholar 

  3. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH (2006) Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 113:898–918

    Article  Google Scholar 

  4. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS (2003) Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289:76–79

    Article  Google Scholar 

  5. Vincent HK, Innes KE, Vincent KR (2007) Oxidative stress and potential interventions to reduce oxidative stress in overweight and obesity. Diabetes Obes Metab 9:813–839

    Article  CAS  Google Scholar 

  6. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867

    Article  CAS  Google Scholar 

  7. Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116:1793–1801

    Article  CAS  Google Scholar 

  8. 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 1790:1149–1160

    Article  CAS  Google Scholar 

  9. Packer L, Kraemer K, Rimbach G (2001) Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17:888–895

    Article  CAS  Google Scholar 

  10. Padmalayam I, Hasham S, Saxena U, Pillarisetti S (2009) Lipoic acid synthase (LASY): a novel role in inflammation, mitochondrial function, and insulin resistance. Diabetes 58:600–608

    Article  CAS  Google Scholar 

  11. 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 65:43–50

    Article  CAS  Google Scholar 

  12. Shen QW, Jones CS, Kalchayanand N, Zhu MJ, Du M (2005) Effect of dietary alpha-lipoic acid on growth, body composition, muscle pH, and AMP-activated protein kinase phosphorylation in mice. J Anim Sci 83:2611–2617

    CAS  Google Scholar 

  13. 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 10:727–733

    Article  CAS  Google Scholar 

  14. 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(85):e81–e88

    Google Scholar 

  15. 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 16:840–846

    Article  CAS  Google Scholar 

  16. Wang Z, Nakayama T (2010) Inflammation, a link between obesity and cardiovascular disease. Mediat Inflamm 2010:535918

    Article  Google Scholar 

  17. Wozniak SE, Gee LL, Wachtel MS, Frezza EE (2009) Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci 54:1847–1856

    Article  Google Scholar 

  18. Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, Richelsen B (2003) Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 285:E527–E533

    CAS  Google Scholar 

  19. Funahashi T, Matsuzawa Y (2006) Hypoadiponectinemia: a common basis for diseases associated with overnutrition. Curr Atheroscler Rep 8:433–438

    Article  CAS  Google Scholar 

  20. Moreno-Aliaga MJ, Lorente-Cebrian S, Martinez JA (2010) Regulation of adipokine secretion by n-3 fatty acids. Proc Nutr Soc 69:324–332

    Article  CAS  Google Scholar 

  21. Kubota N, Terauchi Y, Kubota T, Kumagai H, Itoh S, Satoh H, Yano W, Ogata H, Tokuyama K, Takamoto I, Mineyama T, Ishikawa M, Moroi M, Sugi K, Yamauchi T, Ueki K, Tobe K, Noda T, Nagai R, Kadowaki T (2006) Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J Biol Chem 281:8748–8755

    Article  CAS  Google Scholar 

  22. Cheng PY, Lee YM, Yen MH, Peng JC, Lam KK (2011) Reciprocal effects of alpha-lipoic acid on adenosine monophosphate-activated protein kinase activity in obesity induced by ovariectomy in rats. Menopause 18:1010–1017

    Article  Google Scholar 

  23. Cummings BP, Stanhope KL, Graham JL, Evans JL, Baskin DG, Griffen SC, Havel PJ (2010) Dietary fructose accelerates the development of diabetes in UCD-T2DM rats: amelioration by the antioxidant, alpha-lipoic acid. Am J Physiol Regul Integr Comp Physiol 298:R1343–R1350

    Article  CAS  Google Scholar 

  24. Huong DT, Ide T (2008) Dietary lipoic acid-dependent changes in the activity and mRNA levels of hepatic lipogenic enzymes in rats. Br J Nutr 100:79–87

    Article  CAS  Google Scholar 

  25. Daval M, Foufelle F, Ferre P (2006) Functions of AMP-activated protein kinase in adipose tissue. J Physiol 574:55–62

    Article  CAS  Google Scholar 

  26. Dzamko NL, Steinberg GR (2009) AMPK-dependent hormonal regulation of whole-body energy metabolism. Acta Physiol (Oxf) 196:115–127

    Article  CAS  Google Scholar 

  27. Kola B, Grossman AB, Korbonits M (2008) The role of AMP-activated protein kinase in obesity. Front Horm Res 36:198–211

    Article  CAS  Google Scholar 

  28. Zhang BB, Zhou G, Li C (2009) AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab 9:407–416

    Article  Google Scholar 

  29. Park KG, Min AK, Koh EH, Kim HS, Kim MO, Park HS, Kim YD, Yoon TS, Jang BK, Hwang JS, Kim JB, Choi HS, Park JY, Lee IK, Lee KU (2008) Alpha-lipoic acid decreases hepatic lipogenesis through adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. Hepatology 48:1477–1486

    Article  CAS  Google Scholar 

  30. Targonsky ED, Dai F, Koshkin V, Karaman GT, Gyulkhandanyan AV, Zhang Y, Chan CB, Wheeler MB (2006) Alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells. Diabetologia 49:1587–1598

    Article  CAS  Google Scholar 

  31. Lee WJ, Song KH, Koh EH, Won JC, Kim HS, Park HS, Kim MS, Kim SW, Lee KU, Park JY (2005) Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun 332:885–891

    Article  CAS  Google Scholar 

  32. 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 55:1059–1069

    Article  CAS  Google Scholar 

  33. Bustos M, Beraza N, Lasarte JJ, Baixeras E, Alzuguren P, Bordet T, Prieto J (2003) Protection against liver damage by cardiotrophin-1: a hepatocyte survival factor up-regulated in the regenerating liver in rats. Gastroenterology 125:192–201

    Article  CAS  Google Scholar 

  34. Timmers S, de Vogel-van den Bosch J, Towler MC, Schaart G, Moonen-Kornips E, Mensink RP, Hesselink MK, Hardie DG, Schrauwen P (2010) Prevention of high-fat diet-induced muscular lipid accumulation in rats by alpha lipoic acid is not mediated by AMPK activation. J Lipid Res 51:352–359

    Article  CAS  Google Scholar 

  35. 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 286:60–66

    Article  CAS  Google Scholar 

  36. Masharani U, Gjerde C, Evans JL, Youngren JF, Goldfine ID (2010) Effects of controlled-release alpha lipoic acid in lean, nondiabetic patients with polycystic ovary syndrome. J Diabetes Sci Technol 4:359–364

    Google Scholar 

  37. Orci L, Cook WS, Ravazzola M, Wang MY, Park BH, Montesano R, Unger RH (2004) Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci USA 101:2058–2063

    Article  CAS  Google Scholar 

  38. Hardie DG (2011) Sensing of energy and nutrients by AMP-activated protein kinase. Am J Clin Nutr 93:891S–896S

    Article  CAS  Google Scholar 

  39. Mulligan JD, Gonzalez AA, Stewart AM, Carey HV, Saupe KW (2007) Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse. J Physiol 580:677–684

    Article  CAS  Google Scholar 

  40. Gonzalez-Periz A, Horrillo R, Ferre N, Gronert K, Dong B, Moran-Salvador E, Titos E, Martinez-Clemente M, Lopez-Parra M, Arroyo V, Claria J (2009) Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins. Faseb J 23:1946–1957

    Article  CAS  Google Scholar 

  41. Ziemke F, Mantzoros CS (2010) Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr 91:258S–261S

    Article  CAS  Google Scholar 

  42. Tishinsky JM, Ma DW, Robinson LE (2011) Eicosapentaenoic acid and rosiglitazone increase adiponectin in an additive and PPARgamma-dependent manner in human adipocytes. Obesity (Silver Spring) 19:262–268

    Article  CAS  Google Scholar 

  43. Perez-Matute P, Perez-Echarri N, Martinez JA, Marti A, Moreno-Aliaga MJ (2007) Eicosapentaenoic acid actions on adiposity and insulin resistance in control and high-fat-fed rats: role of apoptosis, adiponectin and tumour necrosis factor-alpha. Br J Nutr 97:389–398

    Article  CAS  Google Scholar 

  44. Zulian A, Cancello R, Girola A, Gilardini L, Alberti L, Croci M, Micheletto G, Danelli P, Invitti C (2011) In vitro and in vivo effects of metformin on human adipose tissue adiponectin. Obes Facts 4:27–33

    Article  CAS  Google Scholar 

  45. Wang Y, Lam KS, Yau MH, Xu A (2008) Post-translational modifications of adiponectin: mechanisms and functional implications. Biochem J 409:623–633

    Article  CAS  Google Scholar 

  46. Lihn AS, Jessen N, Pedersen SB, Lund S, Richelsen B (2004) AICAR stimulates adiponectin and inhibits cytokines in adipose tissue. Biochem Biophys Res Commun 316:853–858

    Article  CAS  Google Scholar 

  47. 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 8:1288–1295

    Article  CAS  Google Scholar 

  48. 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 52:1355–1363

    Article  CAS  Google Scholar 

  49. Henriksen EJ, Diamond-Stanic MK, Marchionne EM (2011) Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med 51:993–999

    Article  CAS  Google Scholar 

  50. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114:1752–1761

    CAS  Google Scholar 

  51. Rudich A, Tirosh A, Potashnik R, Khamaisi M, Bashan N (1999) Lipoic acid protects against oxidative stress induced impairment in insulin stimulation of protein kinase B and glucose transport in 3T3-L1 adipocytes. Diabetologia 42:949–957

    Article  CAS  Google Scholar 

  52. Valdecantos MP, Perez-Matute P, Prieto-Hontoria PL, Sanchez-Campayo E, Moreno-Aliaga MJ, Martinez JA (2011) Erythrocyte antioxidant defenses as a potential biomarker of liver mitochondrial status in different oxidative conditions. Biomarkers 16:670–678

    Article  CAS  Google Scholar 

  53. Valdecantos MP, Perez-Matute P, Gonzalez-Muniesa P, Prieto-Hontoria PL, Moreno-Aliaga MJ, Martinez JA. (2012) Lipoic acid improves mitochondrial function in nonalcoholic steatosis through the stimulation of Sirtuin 1 and Sirtuin 3. Obesity (Silver Spring): doi:10.1038/oby.2012.1032

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Acknowledgments

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.

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The authors state no conflict of interest.

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Correspondence to María J. Moreno-Aliaga.

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Prieto-Hontoria, P.L., Pérez-Matute, P., Fernández-Galilea, M. et al. Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr 52, 779–787 (2013). https://doi.org/10.1007/s00394-012-0384-7

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  • DOI: https://doi.org/10.1007/s00394-012-0384-7

Keywords

  • Lipoic acid
  • Obesity
  • Adiponectin
  • AMPK