Free and protein bound leptin are distinct and independently controlled factors in energy regulation

Aims/hypothesis. Leptin exerts important regulating effects on energy homeo stasis and could have a central role in our understanding of obesity, diabe tes mellitus and the metabolic syndrome. Leptin circulates in a free and pr otein bound form. The aim of the present study was to test whether both fra ctions of the leptin system can be selectively regulated and thus serve ind ependent physiological roles. Methods. Using specific radioimmunoassays we measured both leptin component s in relation to BMI in healthy subjects before and after weight reduction and in hyperthyroid patients during correction of thyrotoxicosis. In the la tter group body composition and resting energy expenditure was monitored. I n addition, we measured serum and cerebrospinal fluid concentrations of fre e and bound leptin in patients with neurological disorders. Results. Under all conditions free leptin concentrations reflected body fat mass. Bound leptin concentrations decreased during weight reduction but al so after treatment of hyperthyroidism despite an increase in fat mass. Dire ct measurement of resting energy expenditure and bound leptin in hyperthyro id patients and under thyrostatic treatment showed a significant positive c orrelation of both variables. In contrast to free leptin whose transport in to the cerebrospinal fluid appears to be saturated at low physiological con centrations of serum free leptin, bound leptin concentrations in the cerebr ospinal fluid increased in parallel to serum concentrations over the whole physiologically relevant range. Conclusion/interpretation. Our data indicate a distinct role of free and bo und leptin in the feedback regulating energy intake and expenditure and cou ld have important implications for our understanding of the physiology and pathophysiology of leptin-dependent signalling.