Deletion of p22phox-dependent oxidative stress in the hypothalamus protects against obesity by modulating β3-adrenergic mechanisms
Heinrich E. Lob, … , Allyn L. Mark, Robin L. Davisson
Heinrich E. Lob, … , Allyn L. Mark, Robin L. Davisson
Published January 26, 2017
Citation Information: JCI Insight. 2017;2(2):e87094. https://doi.org/10.1172/jci.insight.87094.
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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 2

Ablation of p22phox in the periventricular nucleus ameliorates body weight gain independent of food intake, eating behavior, and activity.

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Ablation of p22phox in the periventricular nucleus ameliorates body weig...
(A and B) Body weight gain (A, n = 13–19) and caloric intake (B, n = 8–17) in AdLacZ- or AdCre-treated p22phox/fl mice during 10 weeks of normal chow (NC) or diet-induced obesity (DIO). (C) Weekly food intake in AdLacZ or AdCre mice during 10 weeks of NC or DIO (n = 7–17). (D–G) Food intake (D), feeding frequency (E), average meal size (F), and average meal length (G) measured by indirect calorimetry in AdLacZ- or AdCre-injected p22phox/fl mice over 24 hours (n = 4–8). (H) Spontaneous locomotor activity during the light and dark cycles in AdLacZ and AdCre mice after 10 weeks of NC or high-fat diet (n = 4–8). The gray area indicates the dark cycle between 6 pm and 6 am.*P < 0.05 vs. NC; #P < 0.05 vs. AdLacZ DIO; 2-way ANOVA followed by a Sidak multiple comparison post-hoc test. All data are the mean ± SEM.