Obese patients have high plasma leptin concentrations that do not induce the expected responses on weight regulation, suggesting a leptin resistance in obesity. Elevated leptin levels are also thought to be related to a high sympathetic nervous system (SNS) activity. This effect could be preserved, lowered, or even abolished in obesity. We planned to investigate the possible association in a longitudinal study. Ninety-five normotensive healthy women, aged 40.4 +/- 11.4 years and body mass index of 33.2 +/- 2.3 kg/m(2), were studied. Baseline leptin, fat mass, and heart rate variability were measured and included in a 6-month longitudinal study. Body composition was measured by dual-energy x-ray absorption. Time domain heart rate variability, QT dynamicity, and spectral components on ambulatory electrocardiographs were analyzed. Dietary advice was given by a dietitian to the patient (maximum caloric reduction of 30%), and subjects were randomized in 3 treatment groups: sibutramine 10 mg, sibutramine 20 mg, or placebo. At baseline, low frequencies (LF) and the LF-high frequencies (HF) ratio, mainly related to the SNS, were negatively correlated to leptin concentration (r = -0.30, P = .002 and r = -0.36, P < .001) and to the leptin-fat mass ratio (r = -0.28, P = .004 and r = - 0.33, P = .0007), thus explaining 38% of the LF variance and 33% of the LF/HF variance. Diastolic blood pressure was also negatively correlated to leptin concentrations (-0.20, P = .04) and to the leptin-fat mass ratio (-0.22, P = .022). In contrast, no consistent correlations between leptin and the time domain components related to vagal activity were observed. At 6 months, after completion of the weight loss program, LF significantly decreased (-7.7% +/- 7.9%, P < .001), whereas HF was higher than the initial value (+20% +/- 5.2%). The leptin-fat mass ratio remained negatively correlated to the LF (r = -0.34, P = .030) and to LF/HF (r = -0.35, P = .021) values, explaining 21% of the LF variation. None of the pairwise comparisons between the 2 sibutramine groups and the placebo group were statistically significant for heart rate variability. High leptin concentration is associated with low indexes of cardiac SNS activity and with a lower diastolic blood pressure in normotensive obese women. Our results imply therefore that the relationship between leptin and the autonomic nervous system is disturbed in normotensive obese subjects.