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Br J Pharmacol. 2011 Mar;162(5):1213-24. doi: 10.1111/j.1476-5381.2010.01134.x.

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

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  • 1State Key Laboratory of Medical Genomics, and Department of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Abstract

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.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

PMID:
21108628
[PubMed - indexed for MEDLINE]
PMCID:
PMC3051392
Free PMC Article
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