NOX2 deficiency attenuates markers of adiposopathy and brain injury induced by high-fat diet

Abstract

Pepping JK, Freeman LR, Gupta S, Keller JN, Bruce-Keller AJ. NOX2 deficiency attenuates markers of adiposopathy and brain injury induced by high-fat diet. Am J Physiol Endocrinol Metab 304: E392-E404, 2013. First published December 11, 2012 doi:10.1152/ajpendo.00398.2012.-The consumption of high-fat/ calorie diets in modern societies is likely a major contributor to the obesity epidemic, which can increase the prevalence of cancer, cardiovascular disease, and neurological impairment. Obesity may precipitate decline via inflammatory and oxidative signaling, and one factor linking inflammation to oxidative stress is the proinflammatory, pro-oxidant enzyme NADPH oxidase. To reveal the role of NADPH oxidase in the metabolic and neurological consequences of obesity, the effects of high-fat diet were compared in wild-type C57Bl/6 (WT) mice and in mice deficient in the NAPDH oxidase subunit NOX2 (NOX2KO). While diet-induced weight gains in WT and NOX2KO mice were similar, NOX2KO mice had smaller visceral adipose deposits, attenuated visceral adipocyte hypertrophy, and diminished visceral adipose macrophage infiltration. Moreover, the detrimental effects of HFD on markers of adipocyte function and injury were attenuated in NOX2KO mice; NOX2KO mice had improved glucose regulation, and evaluation of NOX2 expression identified macrophages as the primary population of NOX2-positive cells in visceral adipose. Finally, brain injury was assessed using markers of cerebrovascular integrity, synaptic density, and reactive gliosis, and data show that high-fat diet disrupted marker expression in WT but not NOX2KO mice. Collectively, these data indicate that NOX2 is a significant contributor to the pathogenic effects of high-fat diet and reinforce a key role for visceral adipose inflammation in metabolic and neurological decline. Development of NOX-based therapies could accordingly preserve metabolic and neurological function in the context of metabolic syndrome. brain injury; metabolic syndrome; NADPH oxidase; obesity

Mice lacking NOX2 are hyperphagic and store fat preferentially in the liver

“…The alteration in adipose tissue was depot specific, as we found no genotypeassociated differences in subcutaneous adipose mass; however, and strikingly, NOX2-KO mice did not gain nearly as much epididymal adipose mass as WT mice when challenged with a HF diet. This feature was also observed by Pepping et al (38), but, unlike their findings, the adipocytes of the NOX2-KO mice studied in our study were able to increase their size in response to overnutrition. Moreover, their leptin production was not altered.…”

“…Consistent with our finding, Lee et al (30) found increased inflammation and tissue infiltration of immune cells in NOX2-KO mice compared with WT mice during the development of arthritis. Moreover, Pepping et al found increased macrophage infiltration into EWAT of HF-fed WT mice, but not NOX2-KO mice (38), whereas we found a trend for increased EWAT macrophage infiltration in both chow-and HF-fed NOX2-KO mice compared with WT mice. On the other hand, You et al observed decreased kidney macrophage infiltration in NOX2-KO mice in a model of type 1 diabetes (50) attributed to lower levels of kidney Ccl2 (monocyte chemoattractant protein-1/MCP-1).…”

“…While this study was ongoing, Pepping et al (38) also found that NOX2-KO mice become hyperphagic when on a HF diet, although they failed to see this phenotype in chow-fed mice.…”

Nox2 Mediates Skeletal Muscle Insulin Resistance Induced by a High Fat Diet

“…3B). A recent report showed that Nox2-KO mice fed high fat diet had smaller visceral adipose deposits, attenuated visceral adipocyte hypertrophy, and diminished visceral adipose macrophage infiltration (31). We are currently assessing fat cells to determine further the impact of Nox2 on fat metabolism and oxidative stress.…”

Age-related accumulation of advanced glycation end-products-albumin, S100β, and the expressions of advanced glycation end product receptor differ in visceral and subcutaneous fat

“…The tissues were washed with PBS for three times, incubated with anti-Iba1 antibody at 4 C overnight for activated macrophage labeling [7]. After PBS wash, tissues were incubated with biotinylated secondary antibody and ABC reagent according to manufacturer's manuals (Vector Laboratories, cat.…”