Rector RS, Warner SO, Liu Y, Hinton PS, Sun GY, Cox RH, Stump CS, Laughlin MH, Dellsperger KC, Thomas TR. Exercise and diet induced weight loss improves measures of oxidative stress and insulin sensitivity in adults with characteristics of the metabolic syndrome. Am J Physiol Endocrinol Metab 293: E500-E506, 2007. First published May 1, 2007; doi:10.1152/ajpendo.00116.2007.-Obesity and insulin resistance (IR) increase the risk for coronary heart disease; however, much of this risk is not attributable to traditional risk factors. We sought to determine whether weight loss associated with supervised aerobic exercise beneficially alters biomarkers of oxidative stress and whether these alterations are associated with improvements in measures of insulin resistance. Twenty-five sedentary and overweight to obese [body mass index (BMI) ϭ 33.0 Ϯ 0.8 kg/m 2 ] individuals, with characteristics of the metabolic syndrome, participated in a 4-to 7-mo weight loss program that consisted of energy restriction (reduced by ϳ500 kcal/day) and supervised aerobic exercise (5 days/wk, 45 min/day at 60% V O2 max; ϳ375 kcal/day). IR and insulin sensitivity were assessed by the calculation of the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI), respectively. Oxidative stress was assessed by oxidized LDL (oxLDL), myeloperoxidase (MPO), and low-and high-density lipoprotein (LDL and HDL) lipid hydroperoxide concentrations in serum. Indexes for antioxidative status included apolipoprotein A1 (apoA1) concentrations and paraoxonase-1 (PON1) activity and protein concentrations. Exercise-and diet-induced weight loss (ϳ10%) significantly (P Ͻ 0.05) increased insulin sensitivity and reduced IR, oxLDL, and LDL lipid hydroperoxides but did not alter HDL lipid hydroperoxides or MPO concentrations. Lifestyle modification impacted systemic antioxidative status by increasing apoA1 concentrations and reducing serum PON1 protein and activity. Changes in oxidative stress were not associated with alterations in HOMA or QUICKI. Diet-and exercise-induced weight loss (ϳ10%) improves measures of insulin sensitivity and beneficially alters biomarkers of oxidative status. insulin resistance; oxidized low-density lipoprotein; paraoxonase-1; energy restriction AMERICANS ARE EXPERIENCING a weight gain epidemic, and recent epidemiological studies suggest an increased risk of coronary heart disease (CHD) and type 2 diabetes in overweight and obese individuals. In addition, patients with type 2 diabetes, impaired glucose tolerance, and insulin resistance (IR) are at elevated risk for CHD (24). Despite elevated levels of hypertension, obesity, and dyslipidemia in these individuals, epidemiological studies suggest that traditional risk factors do not explain all of the elevated risk of CHD (24,29). This suggests that other underlying abnormalities are present and contributing to the etiology of the disease.One possible link between IR and CHD is reduced levels of high-density lipoproteins (HDL) and increased oxidative stress....