Deletion of p22^phox-dependent oxidative stress in the hypothalamus protects against obesity by modulating β₃-adrenergic mechanisms

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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 p22^phox, the obligatory subunit for NADPH oxidase activity, in mice harboring a conditional p22^phox allele. Selective deletion of p22^phox 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.

Authors

Heinrich E. Lob, Jiunn Song, Chansol Hurr, Alvin Chung, Colin N. Young, Allyn L. Mark, Robin L. Davisson