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

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.

• Authors: Weili Shen, Jiejie Hao, Zhihui Feng, Chuan Tian, Weijun Chen, Lester Packer, Xianglin Shi, Weijin Zang, Jiankang Liu
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 162 Issue 5 Pg. 1213-24 (Mar 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21108628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• DNA Primers
• DNA, Mitochondrial
• Hypoglycemic Agents
• Mitochondrial Proteins
• PPAR alpha
• PPAR gamma
• RNA, Messenger
• Thioctic Acid
• lipoamide
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Carnitine O-Palmitoyltransferase
• Cyclic GMP-Dependent Protein Kinases
• Cyclic GMP

Topics

• 3T3-L1 Cells
• Adipocytes (drug effects, metabolism)
• Animals
• Base Sequence
• Carnitine O-Palmitoyltransferase (genetics)
• Cyclic GMP (metabolism)
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• DNA Primers (genetics)
• DNA, Mitochondrial (genetics, metabolism)
• Hypoglycemic Agents (pharmacology)
• Mice
• Microscopy, Electron, Transmission
• Mitochondria (drug effects, genetics, metabolism, ultrastructure)
• Mitochondrial Proteins (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Oxygen Consumption (drug effects)
• PPAR alpha (genetics)
• PPAR gamma (genetics)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction (drug effects)
• Thioctic Acid (analogs & derivatives, pharmacology)