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

Weili Shen, Jiejie Hao, Zhihui Feng, Chuan Tian, Weijun Chen, Lester Packer, Xianglin Shi, Weijin Zang, Jiankang Liu

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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.

Original languageEnglish
Pages (from-to)1213-1224
Number of pages12
JournalBritish Journal of Pharmacology
Volume162
Issue number5
DOIs
StatePublished - Mar 2011

Keywords

  • lipoamide
  • lipoic acid
  • mitochondria
  • mitochondrial transcription factor A (TFAM)
  • nuclear respiratory factor 1 (NRF1)
  • peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α)

ASJC Scopus subject areas

  • Pharmacology

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