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Division of Endocrinology, Diabetes, and Metabolism, State University of New York, and Kaleida Health, Buffalo, New York 14209
Address all correspondence and requests for reprints to: Paresh Dandona, M.D., Diabetes-Endocrinology Center of Western New York, 3 Gates Circle, Buffalo, New York 14209. E-mail: pdandona{at}kaleidahealth.org
Increased reactive oxygen species generation by the leukocytes of the
obese may be responsible for increased oxidative injury to lipids and
proteins and, hence, atherosclerosis. We have investigated whether
reactive oxygen species generation by leukocytes and other indexes of
oxidative damage in the body fall with short-term dietary restriction
and weight loss. Nine nondiabetic obese subjects (body mass index,
32.5–64.4 kg/m2), not taking any antioxidants, were put on
a 1000-Cal diet. Fasting blood samples were taken at 0, 1, 2, 3, and 4
weeks and at 12 weeks after the cessation of dietary restriction. Blood
samples were also obtained at 1 and 2 h after administration of
75 g oral glucose at 0 and 4 weeks. Mononuclear cells (MNC) and
polymorphonuclear leukocytes (PMN) were isolated, and reactive oxygen
species generation was measured. Plasma concentrations of
thiobarbituric acid-reactive species (TBARS), 13-hydroxyoctadecadienoic
acid (13-HODE), 9-hydroxyoctadecadienoic acid (9-HODE), carbonylated
proteins, o-tyrosine, and m-tyrosine as
indexes of oxidative damage to lipids, proteins and amino acids,
respectively, were measured. Antioxidant vitamins were measured as
indexes of antioxidant reserves. Plasma tumor necrosis factor-
concentrations were also measured. Mean weight loss was 2.4 ± 0.6
kg at week 1, 2.5 ± 1.7 kg at week 2, 3.9 ± 0.8 kg at week
3, and 4.5 ± 2.8 kg at week 4 (P < 0.05).
Reactive oxygen species generation by PMN fell from 236.4 ± 95.8
to 150.9 ± 69.0, 125.9 ± 24.3, 96.0 ± 39.9, and
103.1 ± 35.7 mV at weeks 1, 2, 3, and 4, respectively
(P < 0.001). It increased 3 months after the
cessation of dietary restriction to 270.0 ± 274.3 mV. Reactive
oxygen species generation by MNC fell from 187.8 ± 75.0 to
101.7 ± 64.5, 86.9 ± 42.8, 63.8 ± 14.3, and 75.1
± 32.2 mV and increased thereafter to 302.0 ± 175.5 mV at 1, 2,
3, 4, and 16 weeks, respectively (P < 0.005).
Reactive oxygen species generation by PMN and MNC increased in response
to glucose; the relative increase was greater at 4 weeks than that at
week 0 due to a fall in the basal levels of reactive oxygen species
generation. Consistent with the fall in reactive oxygen species
generation, there was a reduction in plasma TBARS from 1.68 ±
0.17 µmol/L at week 0 to 1.47 µmol/L at 4 weeks
(P < 0.05). The 13-HODE to linoleic acid ratio
fell from a baseline of 100% to 56.4 ± 36.1% at 4 weeks
(P < 0.05), and the 9-HODE to linoleic acid ratio
fell from a baseline of 100% to 60.5 ± 37.7% at 4 weeks
(P < 0.05). Carbonylated proteins fell from
1.39 ± 0.27 µg/mg protein at week 0 to 1.17 ± 0.12
µg/mg protein at week 4 (P < 0.05);
o-tyrosine fell from 0.42 ± 0.03 mmol/mol
phenylalanine at week 0 to 0.36 ± 0.02 mmol/mol phenylalanine at
4 weeks (P < 0.005), and m-tyrosine
fell from 0.45 ± 0.04 mmol/mol phenylalanine at week 0 to
0.40 ± 0.03 mmol/mol phenylalanine at 4 weeks
(P < 0.05). The basal concentrations of TBARS,
9-HODE, 13-HODE, carbonylated proteins, o-tyrosine, and
m-tyrosine in the obese were significantly greater than
those in normal subjects. On the other hand, tumor necrosis factor-
concentrations did not change during this 4-week period, nor was there
any change in antioxidant vitamins. This is the first demonstration of
1) an increase in reactive oxygen species-induced damage in lipids,
proteins, and amino acids in the obese compared with normal subjects;
and 2) a decrease in reactive oxygen species generation by leukocytes
and oxidative damage to lipids, proteins, and amino acids after dietary
restriction and weight loss in the obese over a short period.
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