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

• Published in: Diabetologia 2008-01, Vol.51 (1), p.165-174
• Main Authors: Shen, W, Liu, K, Tian, C, Yang, L, Li, X, Ren, J, Packer, L, Cotman, C. W, Liu, J
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Acetylcarnitine - pharmacology; Adipocytes - metabolism; Animals; Biological and medical sciences; Carnitine O-Palmitoyltransferase - metabolism; Diabetes. Impaired glucose tolerance; DNA, Mitochondrial - metabolism; Dose-Response Relationship, Drug; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty Acids - metabolism; Gamma coactivator 1 alpha; Human Physiology; Insulin Resistance; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial complex; Mitochondrial transcription factor A; Models, Biological; Nuclear respiratory factor 1; Nuclear respiratory factor 2; Oxygen - metabolism; Peroxisome proliferator-activated receptor; Peroxisome proliferator-activated receptor alpha; Peroxisome proliferator-activated receptor gamma; PPAR alpha - metabolism; PPAR gamma - metabolism; Thioctic Acid - pharmacology
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-007-0852-4

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.