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Increase in Glucose-6-Phosphate Dehydrogenase in Adipocytes Stimulates Oxidative Stress and Inflammatory Signals

¹ Department of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Seoul, Korea
² Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
³ Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

Address correspondence and reprint requests to Jae Bum Kim, PhD, Department of Biological Sciences, Seoul National University, San 56-1, Sillim-Dong, Kwanak-Gu, Seoul, Korea. E-mail: jaebkim{at}snu.ac.kr

Abbreviations: CCR2, chemokine (C-C motif) receptor 2; DCF-DA, 2,7-dichlorodihydrofluorescein diacetate; G6PD, glucose-6-phosphate dehydrogenase; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; IB, inhibitory B; IKK-ß, IB kinase-ß; IL, interleukin; iNOS, inducible nitric oxide synthase; MCP1, monocyte chemoattractant protein 1; NAC, N-acetyl-L-cysteine; NF, nuclear factor; PBST, PBS with Triton X-100; TNF, tumor necrosis factor; ROS, reactive oxygen species; SOD, superoxide dismutase

In adipocytes, oxidative stress and chronic inflammation are closely associated with metabolic disorders, including insulin resistance, obesity, cardiovascular disease, and type 2 diabetes. However, the molecular mechanisms underlying these metabolic disorders have not been thoroughly elucidated. In this report, we demonstrate that overexpression of glucose-6-phosphate dehydrogenase (G6PD) in adipocytes stimulates oxidative stress and inflammatory responses, thus affecting the neighboring macrophages. Adipogenic G6PD overexpression promotes the expression of pro-oxidative enzymes, including inducible nitric oxide synthase and NADPH oxidase, and the activation of nuclear factor-B (NF-B) signaling, which eventually leads to the dysregulation of adipocytokines and inflammatory signals. Furthermore, secretory factors from G6PD-overexpressing adipocytes stimulate macrophages to express more proinflammatory cytokines and to be recruited to the adipocytes; this would cause chronic inflammatory conditions in the adipose tissue of obesity. These effects of G6PD overexpression in adipocytes were abolished by pretreatment with NF-B inhibitors or antioxidant drugs. Thus, we propose that a high level of G6PD in adipocytes may mediate the onset of metabolic disorders in obesity by increasing the oxidative stress and inflammatory signals.

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