Sympathetic-leptin relationship in obesity: effect of weight loss Didier Quilliot a,b, ⁎ , Philip Böhme b , Faiez Zannad a , Olivier Ziegler b a Centre d'Investigation Clinique, INSERM-CHU, Nancy, France b Service de Diabétologie, Maladies Métaboliqueset Nutrition, Hôpital Jeanne d'Arc, Centre Hospitalier Universitaire de NANCY, 54201 Toul cedex, France Received 15 December 2006; accepted 9 November 2007 Abstract 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 b .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 b .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. © 2008 Published by Elsevier Inc. 1. Introduction Obese patients have high plasma leptin concentrations related to the extent of their adipose tissue; however, the elevated leptin level does not induce the expected responses [1] on weight regulation, thus suggesting leptin resistance. Increased leptin and insulin levels are thought to increase sympathetic nervous system (SNS) activity [2] and have been implicated in the hypertension seen in obese subjects [3-6]. In animals, long-term leptin infusions may produce a rise in heart rate and arterial blood pressure [5]. However, in animal models of obesity, the leptin effects on the SNS could be preserved, lowered, or even abolished. Therefore, the effects of leptin on body weight may be separated from those related to the SNS. In the Agouti obese mouse, leptin effects on the cardiovascular system and blood pressure regulation are preserved, despite a well-known leptin resistance in these animals [6,7]. Consequently, leptin resistance may involve food intake regulation and affect, or not, SNS activity. In humans, we suspected that obese subjects who do not develop hypertension could have a resistance to the sympathetic excitatory effects of leptin. As the effect of leptin infusions on the SNS cannot be studied readily, we proposed a study of the relationship between leptin concentrations and cardiovascular sympathetic para- meters as assessed by heart rate variability (HRV) in a group of normotensive obese subjects before and after weight reduction. Available online at www.sciencedirect.com Metabolism Clinical and Experimental 57 (2008) 555 – 562 www.elsevier.com/locate/metabol ⁎ Corresponding author. Centre d'Investigation Clinique, Hôpital Jeanne d'Arc, INSERM-CHU de Nancy, Case Officielle n°34, 54035 Nancy Cedex, France. Tel.: + 33 3 83 65 66 25; fax: + 33 3 83 65 66 19. E-mail address: d.quilliot@chu-nancy.fr (D. Quilliot). 0026-0495/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.metabol.2007.11.020