Lipoamide or lipoic acid stimulates mitochondrial biogenesis in 3T3‐L1 adipocytes via the endothelial NO synthase‐cGMP‐protein kinase G signalling pathway

BACKGROUND AND PURPOSE Metabolic dysfunction due to loss of mitochondria plays an important role in diabetes, and stimulation of mitochondrial biogenesis by anti‐diabetic drugs improves mitochondrial function. In a search for potent stimulators of mitochondrial biogenesis, we examined the effects and mechanisms of lipoamide and α‐lipoic acid (LA) in adipocytes.EXPERIMENTAL APPROACH Differentiated 3T3‐L1 adipocytes were treated with lipoamide or LA. Mitochondrial biogenesis and possible signalling pathways were examined.KEY RESULTS Exposure of 3T3‐L1 cells to lipoamide or LA for 24 h increased the number and mitochondrial mass per cell. Such treatment also increased mitochondrial DNA copy number, protein levels and expression of transcription factors involved in mitochondrial biogenesis, including PGC‐1α, mitochondrial transcription factor A and nuclear respiratory factor 1. Lipoamide produced these effects at concentrations of 1 and 10 µmol·L−1, whereas LA was most effective at 100 µmol·L−1. At 10 µmol·L−1, lipoamide, but not LA, stimulated mRNA expressions of PPAR‐γ, PPAR‐α and CPT‐1α. The potency of lipoamide was 10–100‐fold greater than that of LA. Lipoamide dose‐dependently stimulated expression of endothelial nitric oxide synthase (eNOS) and formation of cGMP. Knockdown of eNOS (with small interfering RNA) prevented lipoamide‐induced mitochondrial biogenesis, which was also blocked by the soluble guanylate cyclase inhibitor, ODQ and the protein kinase G (PKG) inhibitor, KT5823. Thus, stimulation of mitochondrial biogenesis by lipoamide involved signalling via the eNOS‐cGMP‐PKG pathway.CONCLUSIONS AND IMPLICATIONS Our data suggest that lipoamide is a potent stimulator of mitochondrial biogenesis in adipocyte, and may have potential therapeutic application in obesity and diabetes.