Rac1 Is a Possible Link Between Obesity and Oxidative Stress in Chinese Overweight Adolescents

Abstract

Enhanced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in the monocytes occurred in metabolic syndrome, hypertension, diabetes and obese patients in adults. However, whether NADPH oxidase is involved in the oxidative stress of overweight adolescents without comorbidities is still unclear. This study aimed to identify whether and how NADPH oxidase plays a crucial role in overweight adolescents. The study was performed in 93 overweight adolescents and 31 normal weight controls. Moreover, 87 overweight adolescents were enrolled in weight‐loss program. Demographics characteristics, anthropometrics, composition and clinical characteristics were analyzed. Oxidative stress indexes including the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in plasma and the expression of NADPH oxidase in the monocytes were examined. Overweight adolescents showed a higher oxidative stress state, as indicated by decreased SOD activity and elevated MDA level (P < 0.01). Furthermore, increased NADPH oxidase activity in the monocytes was accompanied by Rac1 upregulation. A significant positive bivariate correlation was found between Rac1 expression and MDA (r = 0.289). There also was a significant positive bivariate correlation between Rac1 expression and obesity‐related indexes including BMI (r = 0.227) and percentage of trunk fat (r = 0.233). Data from weight‐loss program reinforced the results. Partial correlation analysis indicated that obesity‐induced oxidative stress and Rac1 expression is a consequence of aberrant glucose‐lipid metabolism in overweight adolescents. In conclusion, we provided novel data showing that NADPH oxidase in the monocytes was highly activated by enhancing Rac1 expression in Chinese overweight adolescents and Rac1 may act as a link between obesity and oxidative stress in overweight adolescents.

Augmented Rac1 Expression and Activity are Associated with Oxidative Stress and Decline of β Cell Function in Obesity

“…As is shown in the current study, in addition to abnormal metabolic status, insulin resistance, and systemic oxidative stress in ob/ob mice, we also found that the ROS production and the expression of Rac1 were significantly increased in the pancreas of ob/ob mice. This result conforms with our former study that Rac1 might play a key role in obesity-related changes [9] and was further confirmed by the specific inhibition of Rac1. After 14 days administration of NSC23766, a specific activity inhibitor of Rac1, the serum levels of fasting glucose and the degree of insulin resistance declined along with the decrease of ROS production and Rac1 expression in pancreas, which suggested that the suppression of Rac1 could decline the oxidative stress level, ameliorate β cell function, and further improve glycometabolism.…”

“…caused by enhancing Rac1 expression and the augmented activity of NADPH oxidase [9]. In the present study, ob/ob mice displayed similar abnormal glucose and lipid metabolism and oxidative stress, which were highly consistent with our previous studies in overweight adolescents [14] and clinical studies that have indicated that obese patients are more susceptible to impaired glucose tolerance and an early-onset diabetes [15].…”

“…Rac1, a small guanosine triphosphate-binding protein that acts as an activator of Nox, has been implicated as playing a modulatory role in Nox-induced oxidative stress and mitochondrial dysfunction that is mostly caused by elevated glucose, lipids or cytokines [7,8]. In our previous study, we found that in monocytes, Nox was highly activated by enhancing Rac1 expression; obesity-induced oxidative stress and Rac1 expression were the consequence of aberrant glucose-lipid metabolism in overweight adolescents [9]. There was evidence that Rac1 contributed to vascular injury and cardiomyocyte apoptosis in the hyperglycemic state in people with diabetes [10], and Rac1 activation might lead to systemic and organic oxidative stress and apoptosis during hyperglycemia [11].…”

Protein prenylation in islet β-cell function in health and diabetes: Putting the pieces of the puzzle together

“…In support of our findings implicating sustained activation of Rac1 in islet b-cell in in vitro and in vivo models of glucolipotoxicity and T2DM are observations by Zhou and associates demonstrating significant increase in the expression and activation of Rac1 in pancreatic tissue from ob/ob mice, a model for obesity; these findings were replicated in insulinsecreting NIT-1b cells under hyper glycemic and hyper lipidemic conditions in vitro [43]. Recently, Sun et al [44] implicated Rac1 as key signaling protein to link obesity and NADPH oxidase derived oxidative stress in Chinese overweight adolescents. Sustained activation of Rac1-Nox2 signaling pathway has been reported in multiple cell types under various pathological conditions including cardiovascular diseases and diabetes [41,45,46].…”

Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders

“…1. Increases in body mass index are associated with increases in circulating aldosterone levels [40], increases in tissue expression of 11β-HSD1 [23] and, in Chinese overweight adolescents, increases in the level of Rac1 expression in monocytes [41]. Weight loss is associated with decreases in aldosterone [42].…”