These authors contributed equally to this work.
Deficiency of NPGPx, an oxidative stress sensor, leads to obesity in mice and human
Article first published online: 4 JUL 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 8, pages 1165–1179, August 2013
How to Cite
Chang, Y.-C., Yu, Y.-H., Shew, J.-Y., Lee, W.-J., Hwang, J.-J., Chen, Y.-H., Chen, Y.-R., Wei, P.-C., Chuang, L.-M. and Lee, W.-H. (2013), Deficiency of NPGPx, an oxidative stress sensor, leads to obesity in mice and human. EMBO Mol Med, 5: 1165–1179. doi: 10.1002/emmm.201302679
See accompanying article 10.1002/emmm.201303094
- Issue published online: 5 AUG 2013
- Article first published online: 4 JUL 2013
- Manuscript Accepted: 3 JUN 2013
- Manuscript Revised: 30 MAY 2013
- Manuscript Received: 26 FEB 2013
- Medical Research Council. Grant Number: G0000934
- Wellcome Trust. Grant Number: 068545/Z/02
- Northern Finland Birth Cohort collection. Grant Number: R01 HL087679
- Academia Sinica, Taiwan to W.H.L.. Grant Number: NSC 97–2314-B-002-047-MY3
- oxidative stress
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.