Myeloid-specific deletion of NOX2 prevents the metabolic and neurologic consequences of high fat diet

• Published in: PloS one Vol. 12; no. 8; p. e0181500
• Main Authors: Pepping, Jennifer K., Vandanmagsar, Bolormaa, Fernandez-Kim, Sun-Ok, Zhang, Jingying, Mynatt, Randall L., Bruce-Keller, Annadora J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.08.2017; Public Library of Science (PLoS)
• Subjects: Adipose tissue; Albinism; Animals; Biology and Life Sciences; Biomedical research; Body Composition - genetics; Body weight; Body Weight - genetics; Brain; Brain - physiology; Brain injury; Cardiovascular disease; Catalysis; Cell injury; Cell Lineage; Cholesterol; Clonal deletion; Cognition; CYBB protein; Data processing; Dementia; Diabetes; Diet; Diet, High-Fat - adverse effects; Gene Deletion; Gene expression; Gene Knockout Techniques; Genetic aspects; Glucose; Head injuries; Health aspects; High fat diet; Infiltration; Inflammation; Inhibition; Insulin resistance; Intra-Abdominal Fat - metabolism; Laboratory animals; Lipids; Macrophages; Medicine and Health Sciences; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Metabolic syndrome; Mice; Monocytes; Myeloid Cells - metabolism; NAD(P)H oxidase; NADPH Oxidase 2; NADPH Oxidases - deficiency; NADPH Oxidases - genetics; NMR; Nuclear magnetic resonance; Nutrition research; Obesity; Oxidases; Oxidizing agents; Pathogenesis; Pathology; Physiological aspects; Rodents; Stem cells; Baton Rouge Louisiana; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0181500

High fat diet-induced obesity is associated with inflammatory and oxidative signaling in macrophages that likely participates in metabolic and physiologic impairment. One key factor that could drive pathologic changes in macrophages is the pro-inflammatory, pro-oxidant enzyme NADPH oxidase. However, NADPH oxidase is a pleiotropic enzyme with both pathologic and physiologic functions, ruling out indiscriminant NADPH oxidase inhibition as a viable therapy. To determine if targeted inhibition of monocyte/macrophage NADPH oxidase could mitigate obesity pathology, we generated mice that lack the NADPH oxidase catalytic subunit NOX2 in myeloid lineage cells. C57Bl/6 control (NOX2-FL) and myeloid-deficient NOX2 (mNOX2-KO) mice were given high fat diet for 16 weeks, and subject to comprehensive metabolic, behavioral, and biochemical analyses. Data show that mNOX2-KO mice had lower body weight, delayed adiposity, attenuated visceral inflammation, and decreased macrophage infiltration and cell injury in visceral adipose relative to control NOX2-FL mice. Moreover, the effects of high fat diet on glucose regulation and circulating lipids were attenuated in mNOX2-KO mice. Finally, memory was impaired and markers of brain injury increased in NOX2-FL, but not mNOX2-KO mice. Collectively, these data indicate that NOX2 signaling in macrophages participates in the pathogenesis of obesity, and reinforce a key role for macrophage inflammation in diet-induced metabolic and neurologic decline. Development of macrophage/immune-specific NOX-based therapies could thus potentially be used to preserve metabolic and neurologic function in the context of obesity.