title: Deficiency of NPGPx, an oxidative stress sensor, leads to obesity in mice and human.
abstract: Elevated oxidative stress is closely associated with obesity. Emerging evidence shows that instead of being a consequence of obesity, oxidative stress may also contribute to fat formation. Nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) is a conserved oxidative stress sensor/transducer and deficiency of NPGPx causes accumulation of reactive oxygen species (ROS). In this communication, we show that NPGPx was highly expressed in preadipocytes of adipose tissue. Deficiency of NPGPx promoted preadipocytes to differentiate to adipocytes via ROS-dependent dimerization of protein kinase A regulatory subunits and activation of CCAAT/enhancer-binding protein beta (C/EBPβ). This enhanced adipogenesis was alleviated by antioxidant N-acetylcysteine (NAC). Consistently, NPGPx-deficient mice exhibited markedly increased fat mass and adipocyte hypertrophy, while treatment with NAC ablated these phenotypes. Furthermore, single nucleotide polymorphisms (SNPs) in human NPGPx gene, which correlated with lower NPGPx expression level in adipose tissue, were associated with higher body mass index (BMI) in several independent human populations. These results indicate that NPGPx protects against fat accumulation in mice and human via modulating ROS, and highlight the importance of targeting redox homeostasis in obesity management.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan; Graduate Program of Translational Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chang
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Yu
authors.forename: Jin-Yuh
authors.initials: JY
authors.lastname: Shew
authors.forename: Wei-Jei
authors.initials: WJ
authors.lastname: Lee
authors.forename: Juey-Jen
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Yen-Hui
authors.initials: YH
authors.lastname: Chen
authors.forename: Yet-Ran
authors.initials: YR
authors.lastname: Chen
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Wei
authors.forename: Lee-Ming
authors.initials: LM
authors.lastname: Chuang
authors.forename: Wen-Hwa
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015992:Body Mass Index; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010544:Peroxidases / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D022782:CCAAT-Enhancer-Binding Protein-beta; D002352:Carrier Proteins; C578349:NPGPx protein, mouse; D017382:Reactive Oxygen Species; D010544:Peroxidases; C558641:GPX7 protein, human; D005979:Glutathione Peroxidase; D000111:Acetylcysteine
keywords: C/EBPβ; N-acetylcysteine; NPGPx; adipogenesis; oxidative stress