Deletion of p22 phox ‐dependent reactive oxygen species (ROS) in the paraventricular nucleus (PVN) protects against diet‐induced obesity (DIO) by increasing thermogenesis and lipolysis.

Oxidative stress is implicated in the onset of obesity. We reported that deletion of p22 phox , the required subunit for NADPH oxidase activity, in the PVN, prevents DIO by increasing energy expenditure and brown adipose tissue (BAT). Here we tested the hypothesis that reducing p22 phox ‐dependent ROS in the PVN protects against DIO by increasing β3‐adrenoreceptor (β3‐AR) activity, thereby enhancing BAT thermogenesis and white adipose tissue (WAT) lipolysis. We performed PVN‐targeted injection of an adenovirus encoding Cre recombinase (AdCre) or control AdLacZ in 6 week old p22 phox/flox mice. Two weeks later, mice were fed a high fat diet (HFD, 42%) for 10 weeks. In AdCre vs AdLacZ treated DIO mice, we observed increases in β3‐AR mRNA (+2.6±0.6 fold, n=4, p<0.05) and PGC‐1α mRNA (+1.6±0.17 fold, n=5, p<0.05) in BAT. Lipolysis of subcutaneous WAT was also increased in AdCre vs AdLacZ DIO mice as measured by hormone‐sensitive lipase (HSL, +2.3±0.5 fold, n=6, p<0.05) and β3‐AR mRNA (+2.7±0.7 fold n=4, p<0.05). Blockade of β3‐AR with SR59230A (i.p., 2 mg/kg/day) reversed the increases in energy expenditure, BAT mass and mRNA levels of PGC‐1α, β3‐AR and HSL in BAT and WAT to AdLacZ levels. These data indicate that disrupting oxidative stress in the PVN during DIO increases β3‐AR in BAT and WAT, thereby increasing thermogenic metabolism and lipolysis and reducing adiposity. 12SDG9160010, HL063887 , HL084207