Deletion of p22^phox-dependent oxidative stress in the hypothalamus protects against obesity by modulating <b>β</b>₃-adrenergic mechanisms.

Abstract

A role for oxidative stress in the brain has been suggested in the pathogenesis of diet-induced obesity (DIO), although the underlying neural regions and mechanisms remain incompletely defined. We tested the hypothesis that NADPH oxidase-dependent oxidative stress in the paraventricular nucleus (PVN), a hypothalamic energy homeostasis center, contributes to the development of DIO. Cre/LoxP technology was coupled with selective PVN adenoviral microinjection to ablate <i>p22^phox</i> , the obligatory subunit for NADPH oxidase activity, in mice harboring a conditional <i>p22^phox</i> allele. Selective deletion of <i>p22^phox</i> in the PVN protected mice from high-fat DIO independent of changes in food intake or locomotor activity. This was accompanied by β₃-adrenoceptor-dependent increases in energy expenditure, elevations in brown adipose tissue thermogenesis, and browning of white adipose tissue. These data reveal a potentially novel role for brain oxidative stress in the development of DIO by modulating β₃-adrenoceptor mechanisms and point to the PVN as an underlying neural site.