Dysregulation of adipose glutathione peroxidase 3 in obesity contributes to local and systemic oxidative stress.
Glutathione peroxidase 3 (GPx3) accounts for the major antioxidant activity in the plasma. Here, we demonstrate that down-regulation of GPx3 in the plasma of obese subjects is associated with adipose GPx3 dysregulation, resulting from the increase of inflammatory signals and oxidative stress. Although GPx3 was abundantly expressed in kidney, lung, and adipose tissue, we observed that GPx3 expression was reduced selectively in the adipose tissue of several obese animal models as decreasing plasma GPx3 level. Adipose GPx3 expression was greatly suppressed by prooxidative conditions such as high levels of TNFalpha and hypoxia. In contrast, the antioxidant N-acetyl cysteine and the antidiabetic drug rosiglitazone increased adipose GPx3 expression in obese and diabetic db/db mice. Moreover, GPx3 overexpression in adipocytes improved high glucose-induced insulin resistance and attenuated inflammatory gene expression whereas GPx3 neutralization in adipocytes promoted expression of proinflammatory genes. Taken together, these data suggest that suppression of GPx3 expression in the adipose tissue of obese subjects might constitute a vicious cycle to expand local reactive oxygen species accumulation in adipose tissue potentially into systemic oxidative stress and obesity-related metabolic complications.
Lee
Yun Sok
YS
Institute of Molecular Biology and Genetics, Seoul National University, San 56-1, Sillim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
Kim
A Young
AY
Choi
Jin Woo
JW
Kim
Min
M
Yasue
Shintaro
S
Son
Hee Jung
HJ
Masuzaki
Hiroaki
H
Park
Kyong Soo
KS
Kim
Jae Bum
JB
D041721:3T3-L1 Cells; D000111:Acetylcysteine / Q000494:pharmacology; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001483:Base Sequence; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005979:Glutathione Peroxidase / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000235:genetics; D007668:Kidney / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D018384:Oxidative Stress; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000975:Antioxidants; D008070:Lipopolysaccharides; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; C116888:Gpx3 protein, mouse; D005979:Glutathione Peroxidase; D000111:Acetylcysteine