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 5

p22phox deletion in the PVN elevates thermogenesis and promotes increased expression of Ucp-1 and Pgc-1α in iBAT and browning of scWAT.

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p22phox deletion in the PVN elevates thermogenesis and promotes increas...
(A) Average oxygen consumption (VO2) and (B) heat production in AdLacZ- and AdCre-treated p22phox/fl mice after 10 weeks normal chow (NC) or diet-induced obesity (DIO). *P < 0.05 vs. NC and AdLacZ DIO; #P < 0.05 Dark vs. Light Cycle; n = 4–8. Gray area indicates dark cycle between 6 pm and 6 am. (C) Ucp-1 mRNA expression in interscapular brown adipose tissue (iBAT). *P < 0.05 vs. NC, n = 10–16. (D) Expression of thermogenic marker Pgc-1α in iBAT (n = 10–16). *P < 0.05 vs. NC and AdLacZ DIO; #P < 0.05 vs. NC. (E) Expression of Ucp-1, Pgc-1α, Prdm16, and Hsl mRNA in subcutaneous white adipose tissue (scWAT) in AdLacZ and AdCre mice after 10 weeks NC or high-fat diet (n = 11). *P < 0.05 vs. NC and AdLacZ DIO. All data are the mean ± SEM. All P values determined by 1-way ANOVA followed by Tukey’s post-hoc test.