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


METHODS
Differentiated 3T3-L1 adipocytes were treated with lipoamide or LA. Mitochondrial biogenesis and possible signalling pathways were examined.


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
Our data suggest that lipoamide is a potent stimulator of mitochondrial biogenesis in adipocyte, and may have potential therapeutic application in obesity and diabetes.
State Key Laboratory of Medical Genomics, and Department of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Weili
W
Shen
Jiejie
J
Hao
Zhihui
Z
Feng
Chuan
C
Tian
Weijun
W
Chen
Lester
L
Packer
Xianglin
X
Shi
Weijin
W
Zang
Jiankang
J
Liu
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*
D017931:DNA Primers; D004272:DNA, Mitochondrial; D007004:Hypoglycemic Agents; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D008063:Thioctic Acid; C013091:lipoamide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D002334:Carnitine O-Palmitoyltransferase; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP