Alessandro Pontillo

CONTEXT: Obesity is an independent risk factor for cardiovascular disease, which may be mediated by increased secretion of proinflammatory cytokines by adipose tissue. OBJECTIVE: To determine the effect of a program of changes in lifestyle designed to obtain a sustained reduction of body weight on markers of systemic vascular inflammation and insulin resistance. DESIGN AND SETTING: Randomized single-blind trial conducted from February 1999 to February 2002 at a university hospital in Italy. PATIENTS: One hundred twenty premenopausal obese women (body mass index > or =30) aged 20 to 46 years without diabetes, hypertension, or hyperlipidemia. INTERVENTIONS: The 60 women randomly assigned to the intervention group received detailed advice about how to achieve a reduction of weight of 10% or more through a low-energy Mediterranean-style diet and increased physical activity. The control group (n = 60) was given general information about healthy food choices and exercise. MAIN OUTCOME MEASURES: Lipid and glucose intake; blood pressure; homeostatic model assessment of insulin sensitivity; and circulating levels of interleukin 6 (IL-6), interleukin 18 (IL-18), C-reactive protein (CRP), and adiponectin. RESULTS: After 2 years, women in the intervention group consumed more foods rich in complex carbohydrates (9% corrected difference; P<.001), monounsaturated fat (2%; P =.009), and fiber (7 g/d; P<.001); had a lower ratio of omega-6 to omega-3 fatty acids (-5; P<.001); and had lower energy (-310 kcal/d; P<.001), saturated fat (-3.5%; P =.007), and cholesterol intake (-92 mg/d; P<.001) than controls. Body mass index decreased more in the intervention group than in controls (-4.2; P<.001), as did serum concentrations of IL-6 (-1.1 pg/mL; P =.009), IL-18 (-57 pg/mL; P =.02), and CRP (-1.6 mg/L; P =.008), while adiponectin levels increased significantly (2.2 microg/mL; P =.01). In multivariate analyses, changes in free fatty acids (P =.008), IL-6 (P =.02), and adiponectin (P =.007) levels were independently associated with changes in insulin sensitivity. CONCLUSION: In this study, a multidisciplinary program aimed to reduce body weight in obese women through lifestyle changes was associated with a reduction in markers of vascular inflammation and insulin resistance.

The potential role of anti-inflammatory cytokines in human obesity is unknown. We tested the hypothesis that low serum IL-10 concentrations associate with the metabolic syndrome in obese women. Compared with 50 matched nonobese women, the prevalence of the metabolic syndrome (>/=3 of the following abnormalities: waist circumference, >88 cm; triglycerides, >1.69 mmol/liter; high density lipoprotein cholesterol, <1.29 mmol/liter; blood pressure, >130/85 mm Hg; glucose, >6.1 mmol/liter) was higher in 50 obese women (52% vs. 16%; P < 0.01). As a group, obese women had higher circulating levels of IL-6, C-reactive protein, and IL-10 than nonobese women. In both obese and nonobese women, IL-10 levels were lower in those with than in women without the metabolic syndrome: obese, 1.3 (0.7/2.1) pg/ml vs. 4.5 (4.3/7.4) pg/ml (median and quartiles; P < 0.01); and nonobese, 0.9 (0.7/1.3) pg/ml vs. 1.3 (0.9/3.3) pg/ml (P < 0.05). After 12 months of a lifestyle program, body weight decreased by 10.9 +/- 1.7 kg and was associated with a significant decrement of IL-6, C-reactive protein, and IL-10 levels; the decrease in IL-10 levels was confined to obese women without the metabolic syndrome. These results show that circulating levels of the anti-inflammatory cytokine IL-10 are elevated in obese women and that low IL-10 levels are associated with the metabolic syndrome.

Obesity is associated with an increased risk of developing atherosclerosis, which may be mediated, at least in part, by increased secretion of proinflammatory cytokines by adipose tissue. We examined the hypothesis that circulating levels of IL-18 were elevated in obese women and would be reduced by weight loss. In a sample of 40 obese (body mass index, 36.4 +/- 3.1 kg/m(2)) women we found that plasma IL-18 levels were higher than in 40 normal weight control women (P < 0.01) and were positively associated with body weight (r = 0.46; P < 0.01) and visceral fat (waist to hip ratio; r = 0.39; P < 0.01). Caloric restriction-induced weight loss (> or = 10% of original weight) over 1 yr reduced IL-18 levels from 247 (204/309) to 147 (111/210) pg/ml (medians and 25%/75%; P < 0.01), positively associated with changes in body mass index and waist to hip ratio. In obese women, IL-18 levels are associated with body weight and abdominal fat deposition; weight loss is an important intervention to reduce IL-18 levels. IL-18 may be a novel cytokine operating in human obesity.

THE RATE OF OBESITY AND THE numbers of dieters are increasing in parallel. More than 54 million Americans are currently dieting, yet the epidemic of obesity continues virtually unabated with no sign of reversal. Obesity is an independent risk factor for cardiovascular disease. Adipocytes synthesize and secrete several cytokines, including tumor necrosis factor , interleukin 6 (IL-6), and adiponectin, the latter being one of the most abundant adipose tissue–specific adipocytokines. Elevated levels of several proinflammatory cytokines, such as IL-6, IL-18, and tumor necrosis factor , as well as the sensitive marker of inflammation C-reactive protein (CRP), have been found associated with proxy indicators of elevated body fat (body weight and body mass index [BMI], calculated as weight in kilograms divided by the square of height in meters) and with cardiovascular disease risk factors. Moreover, several proinflammatory molecules, including CRP, IL-6, and IL-18, have been prospectively associated with thrombotic cardiovascular events. For the present study in obese women, we measured the serum concentrations of IL-6, IL-18, and CRP, as well as adiponectin, the novel adipocytokine with anti-inflammatory and insulinsensitizing properties, and their rela-

OBJECTIVE: We describe associations among the heart-rate-corrected QT (QTc) interval, QTc dispersion (QTc-d), circadian BP variation, and autonomic function in obese normotensive women and the effect of sustained weight loss. RESEARCH METHODS AND PROCEDURES: In 71 obese (BMI = 37.14 +/- 2.6 kg/m(2)) women, 25 to 44 years of age, circadian BP variations (24-hour ambulatory BP monitoring), autonomic function (power spectral analysis of RR interval oscillations), and cardiac repolarization times (QTc-d and QTc interval) were recorded at baseline and after 1 year of a multidisciplinary program of weight reduction. RESULTS: Compared with nonobese age-matched women (n = 28, BMI = 23 +/- 2.0 kg/m(2)), obese women had higher values of QTc-d (p < 0.05) and QTc (p < 0.05), an altered sympathovagal balance (ratio of low-frequency/high-frequency power, p < 0.01), and a blunted nocturnal drop in BP (p < 0.01). In obese women, QTc-d and the QTc interval correlated with diastolic nighttime BP (p < 0.01) and sympathovagal balance (p < 0.01). Waist-to-hip ratio, free fatty acids, and plasma insulin levels correlated with QT intervals and reduced nocturnal drops in both systolic and diastolic BP and sympathovagal balance (p < 0.01). After 1 year, obese women lost at least 10% of their original weight, which was associated with decrements of QTc-d (p < 0.02), the QTc interval (p < 0.05), nighttime BP (p < 0.01), and sympathovagal balance (p < 0.02). DISCUSSION: Sustained weight loss is a safe method to ameliorate diastolic nighttime BP drop and sympathetic overactivity, which may reduce the cardiovascular risk in obese women.