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Diabetologia

Erschienen in:

01.01.2008 | Article

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

verfasst von: W. Shen, K. Liu, C. Tian, L. Yang, X. Li, J. Ren, L. Packer, C. W. Cotman, J. Liu

Erschienen in: Diabetologia | Ausgabe 1/2008

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Abstract

Aims/hypothesis

The aim of the study was to address the importance of mitochondrial function in insulin resistance and type 2 diabetes, and also to identify effective agents for ameliorating insulin resistance in type 2 diabetes. We examined the effect of two mitochondrial nutrients, R-α-lipoic acid (LA) and acetyl-l-carnitine (ALC), as well as their combined effect, on mitochondrial biogenesis in 3T3-L1 adipocytes.

Methods

Mitochondrial mass and oxygen consumption were determined in 3T3-L1 adipocytes cultured in the presence of LA and/or ALC for 24 h. Mitochondrial DNA and mRNA from peroxisome proliferator-activated receptor gamma and alpha (Pparg and Ppara) and carnitine palmitoyl transferase 1a (Cpt1a), as well as several transcription factors involved in mitochondrial biogenesis, were evaluated by real-time PCR or electrophoretic mobility shift (EMSA) assay. Mitochondrial complexes proteins were measured by western blot and fatty acid oxidation was measured by quantifying CO₂ production from [1-¹⁴C]palmitate.

Results

Treatments with the combination of LA and ALC at concentrations of 0.1, 1 and 10 μmol/l for 24 h significantly increased mitochondrial mass, expression of mitochondrial DNA, mitochondrial complexes, oxygen consumption and fatty acid oxidation in 3T3L1 adipocytes. These changes were accompanied by an increase in expression of Pparg, Ppara and Cpt1a mRNA, as well as increased expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (Ppargc1a), mitochondrial transcription factor A (Tfam) and nuclear respiratory factors 1 and 2 (Nrf1 and Nrf2). However, the treatments with LA or ALC alone at the same concentrations showed little effect on mitochondrial function and biogenesis.

Conclusions/interpretation

We conclude that the combination of LA and ALC may act as PPARG/A dual ligands to complementarily promote mitochondrial synthesis and adipocyte metabolism.

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Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407PubMedCrossRef

Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307:384–387PubMedCrossRef

Choo HJ, Kim JH, Kwon OB et al (2006) Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 49:784–791PubMedCrossRef

Kersten S, Desvergne B, Wahli W (2000) Roles of PPARs in health and disease. Nature 405:421–424PubMedCrossRef

Lehrke M, Lazar MA (2005) The many faces of PPARgamma. Cell 123:993–999PubMedCrossRef

Li P, Zhu Z, Lu Y, Granneman JG (2005) Metabolic and cellular plasticity in white adipose tissue II: role of peroxisome proliferator-activated receptor-alpha. Am J Physiol Endocrinol Metab 289:E617–E626PubMedCrossRef

Wu H, Kanatous SB, Thurmond FA et al (2002) Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296:349–352PubMedCrossRef

Roden M (2005) Muscle triglycerides and mitochondrial function: possible mechanisms for the development of type 2 diabetes. Int J Obes (Lond) 29 (Suppl 2):S111–S115CrossRef

McCarty MF (2005) Up-regulation of PPARgamma coactivator-1alpha as a strategy for preventing and reversing insulin resistance and obesity. Med Hypotheses 64:399–407PubMedCrossRef

10.

Flachs P, Horakova O, Brauner P et al (2005) Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce beta-oxidation in white fat. Diabetologia 48:2365–2375PubMedCrossRef

11.

Kukidome D, Nishikawa T, Sonoda K et al (2006) Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55:120–127PubMedCrossRef

12.

Wilson-Fritch L, Burkart A, Bell G et al (2003) Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol Cell Biol 23:1085–1094PubMedCrossRef

13.

Wilson-Fritch L, Nicoloro S, Chouinard M et al (2004) Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest 114:1281–1289PubMedCrossRef

14.

Bogacka I, Ukropcova B, McNeil M, Gimble JM, Smith SR (2005) Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro. J Clin Endocrinol Metab 90:6650–6656PubMedCrossRef

15.

Granneman JG, Li P, Zhu Z, Lu Y (2005) Metabolic and cellular plasticity in white adipose tissue I: effects of beta3-adrenergic receptor activation. Am J Physiol Endocrinol Metab 289:E608–E616PubMedCrossRef

16.

Schreiber SN, Emter R, Hock MB et al (2004) The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc Natl Acad Sci USA 101:6472–6477PubMedCrossRef

17.

Bonnefont-Rousselot D (2004) The role of antioxidant micronutrients in the prevention of diabetic complications. Treat Endocrinol 3:41–52PubMedCrossRef

18.

Ames BN, Suh JH, Liu J (2005) Enzymes lose binding affinity for coenzymes and substrates with age: a strategy for remediation. In: Kaput J (ed) Nutrigenomics: concepts and technologies. Wiley, Holboken, NJ, pp 277–291

19.

Haramaki N, Han D, Handelman GJ, Tritschler HJ, Packer L (1997) Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid. Free Radic Biol Med 22:535–542PubMedCrossRef

20.

van der Goes A, Brouwer J, Hoekstra K, Roos D, van den Berg TK, Dijkstra CD (1998) Reactive oxygen species are required for the phagocytosis of myelin by macrophages. J Neuroimmunol 92:67–75PubMedCrossRef

21.

Estrada DE, Ewart HS, Tsakiridis T et al (1996) Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes 45:1798–1804PubMedCrossRef

22.

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 278:34823–34833PubMedCrossRef

23.

Moini H, Packer L, Saris NE (2002) Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. Toxicol Appl Pharmacol 182:84–90PubMedCrossRef

24.

Pershadsingh HA (2007) Alpha-lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome. Expert Opin Investig Drugs 16:291–302PubMedCrossRef

25.

Liu J, Atamna H, Kuratsune H, Ames BN (2002) Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann NY Acad Sci 959:133–166PubMedCrossRef

26.

Hagen TM, Huang S, Curnutte J et al (1994) Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc Natl Acad Sci USA 91:12808–12812PubMedCrossRef

27.

Liu J, Head E, Gharib AM et al (2002) Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-l-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci USA 99:2356–2361PubMedCrossRef

28.

Liu J, Killilea DW, Ames BN (2002) Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-l-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci USA 99:1876–1881PubMedCrossRef

29.

Da Ros R, Assaloni R, Ceriello A (2005) Molecular targets of diabetic vascular complications and potential new drugs. Curr Drug Targets 6:503–509PubMedCrossRef

30.

Adriaensen H, Plaghki L, Mathieu C, Joffroy A, Vissers K (2005) Critical review of oral drug treatments for diabetic neuropathic pain—clinical outcomes based on efficacy and safety data from placebo-controlled and direct comparative studies. Diabetes Metab Res Rev 21:231–240PubMedCrossRef

31.

Mingrone G (2004) Carnitine in type 2 diabetes. Ann NY Acad Sci 1033:99–107PubMedCrossRef

32.

Hayakawa T, Noda M, Yasuda K et al (1998) Ethidium bromide-induced inhibition of mitochondrial gene transcription suppresses glucose-stimulated insulin release in the mouse pancreatic beta-cell line betaHC9. J Biol Chem 273:20300–20307PubMedCrossRef

33.

Boudina S, Sena S, O’Neill BT, Tathireddy P, Young ME, Abel ED (2005) Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation 112:2686–2695PubMedCrossRef

34.

Kanazawa A, Nishio Y, Kashiwagi A, Inagaki H, Kikkawa R, Horiike K (2002) Reduced activity of mtTFA decreases the transcription in mitochondria isolated from diabetic rat heart. Am J Physiol Endocrinol Metab 282:E778–E785PubMed

35.

Thupari JN, Landree LE, Ronnett GV, Kuhajda FP (2002) C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity. Proc Natl Acad Sci USA 99:9498–9502PubMed

36.

Gulick T, Cresci S, Caira T, Moore DD, Kelly DP (1994) The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci USA 91:11012–11016PubMedCrossRef

37.

Bogacka I, Xie H, Bray GA, Smith SR (2005) Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54:1392–1399PubMedCrossRef

38.

Akhand AA, Du J, Liu W et al (2002) Redox-linked cell surface-oriented signaling for T-cell death. Antioxid Redox Signal 4:445–454PubMedCrossRef

39.

Gao J, Zhu ZR, Ding HQ, Qian Z, Zhu L, Ke Y (2007) Vulnerability of neurons with mitochondrial dysfunction to oxidative stress is associated with down-regulation of thioredoxin. Neurochem Int 50:379–385PubMedCrossRef

40.

Hagen TM, Liu J, Lykkesfeldt J et al (2002) Feeding acetyl-l-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA 99:1870–1875PubMedCrossRef

41.

Liu J, Ames BN (2005) Reducing mitochondrial decay with mitochondrial nutrients to delay and treat cognitive dysfunction, Alzheimer’s disease, and Parkinson’s disease. Nutr Neurosci 8:67–89PubMedCrossRef

42.

Hagen TM, Ingersoll RT, Wehr CM et al (1998) Acetyl-l-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci USA 95:9562–9566PubMedCrossRef

Titel: R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes
verfasst von: W. Shen
K. Liu
C. Tian
L. Yang
X. Li
J. Ren
L. Packer
C. W. Cotman
J. Liu
Publikationsdatum: 01.01.2008
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 1/2008
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-007-0852-4

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R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

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