Leptin exists in a free form and a receptor-bound form. Protein-bound rather than free leptin levels may be associated with regulation of muscle sympathetic nerve activity (MSNA). We determined MSNA and bound leptin concentrations in 25 men [age, 29 ؎ 6 yr, body mass index (BMI), 24 ؎ 3 kg/m 2 ]. Baroreflex sensitivity was measured using phenylephrine and nitroprusside infusions. We measured bound leptin in patients with central (multiple system atrophy, n ‫؍‬ 8; age, 59 ؎ 8 yr; BMI, 23 ؎ 2

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... 2 ) and peripheral autonomic failure (pure autonomic failure, n ‫؍‬ 4; age, 71 ؎ 10 yr; BMI, 25 ؎ 3 kg/m 2 ). MSNA was correlated with protein-bound leptin concentrations (r 2 ‫؍‬ 0.35; P < 0.01) but not with free leptin levels (r 2 ‫؍‬ 0.09). MSNA at baseline was 15 ؎ 2 bursts ؋ minutes ؊1 in subjects with lower and 24 ؎ 3 bursts ؋ minutes ؊1 in subjects with higher bound leptin concentrations (P < 0.05). Blood pressure as well as baroreflex regulation of heart rate and MSNA was similar in both groups. Phenylephrine and nitroprusside responses were similar. Patients with multiple system atrophy and autonomic failure featured similar bound leptin levels. We conclude that protein-bound rather than free leptin levels are correlated with basal sympathetic outflow in normotensive, nonobese men. This relationship cannot be explained by a direct central nervous effect of protein-bound leptin. Instead, protein-bound leptin may increase sympathetic vasomotor tone indirectly via a baroreflex mechanism. (J Clin Endocrinol Metab 88: [4955][4956][4957][4958][4959] 2003)