Deletion of p22phox-dependent oxidative stress in the hypothalamus protects against obesity by modulating β3-adrenergic mechanisms
Heinrich E. Lob, Jiunn Song, Chansol Hurr, Alvin Chung, Colin N. Young, Allyn L. Mark, Robin L. Davisson
Heinrich E. Lob, Jiunn Song, Chansol Hurr, Alvin Chung, Colin N. Young, Allyn L. Mark, Robin L. Davisson
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Research Article Metabolism Neuroscience

Deletion of p22phox-dependent oxidative stress in the hypothalamus protects against obesity by modulating β3-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 p22phox, the obligatory subunit for NADPH oxidase activity, in mice harboring a conditional p22phox allele. Selective deletion of p22phox 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

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Figure 1

AdCre targeted to the PVN of p22phox/fl mice is effective and selective in blunting p22phox mRNA and DIO-induced production of ROS in this hypothalamic region.

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AdCre targeted to the PVN of p22phox/fl mice is effective and selective ...
(A) Effects of periventricular nucleus–targeted (PVN-targeted) AdCre or AdLacZ on p22phox expression in the PVN, arcuate nucleus (ARC), and cerebral cortex (CTX) in normal chow–fed (NC-fed) and diet-induced obesity (DIO) p22phox/fl mice. *P < 0.05 vs. NC; #P < 0.05 AdCre vs. AdLacZ; n = 5–6. (B) Representative images of dihydroethidium (DHE) fluorescence in the PVN of p22phox/fl mice that were microinjected with AdLacZ (left panels) or AdCre (right panels) and received 10 weeks NC (upper panels) or high-fat diet (lower panels). Scale bars: 100 μm. (C) Mean DHE fluorescence intensity. *P < 0.05 vs. NC; #P < 0.05 AdCre DIO vs. AdLacZ DIO; n = 4–7. All data are the mean ± SEM. All P values determined by 1-way ANOVA followed by Tukey’s post-hoc test.