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 6

Increased energy expenditure after p22phox deletion in the periventricular nucleus is due to Adrb3-mediated mechanisms.

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Increased energy expenditure after p22phox deletion in the periventricul...
(A and B) Norepinephrine levels in interscapular brown adipose tissue (iBAT) and subcutaneous white adipose tissue (scWAT) of AdLacZ- and AdCre-treated p22phox/fl mice after 10 weeks of high-fat diet (HFD) or normal chow (NC). *P < 0.05 vs. NC; #P < 0.05 AdCre diet-induced obesity (DIO) vs. AdLacZ DIO; n = 3–4. (C) Adrb3 mRNA expression in iBAT and scWAT in AdLacZ- and AdCre-treated mice after 10 weeks of NC or HFD. *P < 0.05 vs. NC and AdLacZ DIO; n = 4–6. (D–H) Effect of SR59230A (i.p.) on Adrb3 in iBAT and scWAT (D), oxygen consumption (VO2) (E), heat production (F), food intake (G), and spontaneous locomotor activity (H) in AdLacZ or AdCre DIO animals during 3 days of SR59230A injections (n = 5–6). *P < 0.05 AdCre DIO vehicle vs. AdLacZ DIO vehicle; #P < 0.05 AdCre DIO SR59230A vs. AdCre DIO vehicle. The gray area indicates the dark cycle between 6 pm and 6 am. All data are the mean ± SEM. All P values determined by 1-way ANOVA followed by Tukey’s post-hoc test.