| Summary: | Oxidative stress attributable to the activation of a Nox2-containing NADPH oxidase is involved in dietary obesity-associated cardiovascular diseases. However, the mechanism of Nox2 activation in dietary obesity remains unclear. In this project age-matched apolipoprotein E knockout (ApoEKO) and Nox2/ApoE double knockout (D-KO) mice were used to investigate high-fat diet (HFD)-induced obesity-related metabolic disorders, Nox2 activation, endothelial and adipose tissue dysfunction. Compared to NCD, HFD ApoEKO mice developed insulin resistance, increased systemic oxidative stress and vascular dysfunction which was accompanied by increased Nox2 expression, activated mitogen-activated protein kinase (MAPK) and attenuated Akt/endothelial nitric oxide synthesis (eNOS) pathways. Akt was decreased, vascular cell adhesion molecule-1 was increased and macrophages were recruited indicating endothelial cell activation and inflammation, attenuating the phosphatidylinositol-3-kinase/Akt/eNOS branch in favour of the MAPK. In vitro experiments showed that in response to high glucose/insulin challenge, ApoEKO aortas increased significantly the levels of Nox2 expression, activation of stress signalling pathways and the cells were senescent. Finally, the relationship of Nox2-derived reactive oxygen species due to obesity and adipose tissue dysfunction was examined for the first time in ApoEKO mice. It was found that adipose tissue in obesity is infiltrated by macrophages and intercellular adhesion molecule-1 is increased. Insulin receptor is decreased whereas ERK phosphorylation is increased and eNOS phosphorylation is decreased suggesting impaired insulin signalling. Uncoupled protein-1 levels also decreased. Nox2/ApoE D-KO mice did not exhibit any of the delirious effects of HFD/ insulin resistance and were protected from adipose tissue inflammation. In conclusion, this project demonstrated a crucial role for metabolic disorders in systemic Nox2 activation, inflammation, endothelial dysfunction and insulin receptor function in HFD ApoEKO mice. Also, it provides novel insights into mechanisms underlying adipose tissue dysfunction. Therefore, Nox2 targeting may represent an effective therapy to preserve endothelial and adipose tissue function and improve global metabolism in dietary obesity.
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