p22phox in the paraventricular nucleus (PVN) of the brain contributes to diet‐induced obesity (DIO)

Oxidative stress is implicated in obesity and obesity‐hypertension, but most studies have focused on peripheral adipose and cardiovascular tissues. Recently, a role for brain NADPH oxidase (Nox) has begun to emerge in DIO. We tested the hypothesis that Nox activity in the PVN, a key energy and cardiovascular homeostasis center of the brain, is causally linked to DIO. Mice harboring a floxed allele of p22 phox , the required subunit for Nox assembly and activity, underwent bilateral PVN‐targeted injection of an adenovirus encoding Cre recombinase (AdCre) to delete PVN p22 phox or control red fluorescent protein (AdRFP). After recovery, mice were fed high fat diet (HFD, 42%) for 8 weeks. Ablation of p22 phox in the PVN with AdCre blunted HFD‐induced increases in body weight compared to AdRFP‐injected mice (AdRFP: +11.46±0.49g vs AdCre: +6.9±0.57g, n = 3, p<0.05). Real‐time qPCR confirmed p22 phox deletion in PVN. Since Nox is functionally linked to endoplasmic reticulum (ER) stress pathways in some cell types, we examined the effect of deleting p22 phox on ER stress biomarkers in PVN of these mice. Preliminary data show that mice with PVN‐targeted ablation of p22 phox have lower levels of HFD‐induced GRP78 (−68%, n=2) and GRP94 (−38%, n=2) mRNA in this brain region compared to controls. These data suggest that oxidative and ER stress in the PVN contribute to diet‐induced obesity. HL063887 , HL084207