An oxidative stress paradox: time for a conceptual change?

Oxidative stress has long been considered a key driving factor of many obesity-related health problems. However, recent work by Merry, Tran et al (Diabetologia DOI 10.1007/s00125-016-4084-3 ) challenges this idea with an interesting study using a hepatocyte-specific Gpx1-knockout (HGKO) mouse. GPX1 is an important detoxification enzyme that converts H2O2 to water. The authors found that high-fat diet-fed HGKO mice were more insulin sensitive than wildtype controls, despite elevated hepatic levels of H2O2 and evidence of increased systemic oxidative stress. When challenged with a non-alcoholic steatohepatitis (NASH)-inducing diet, HGKO mice were also protected, displaying reduced levels of inflammation and fibrosis with similar levels of steatosis compared with controls. These findings call into question the role of reactive oxygen species in NASH pathogenesis and highlight a potential paradox whereby increased H2O2 may be beneficial in some contexts.