Leptin responsiveness of juvenile rats: proof of leptin function within the physiological range.

To bridge the gap between studies demonstrating leptin's role in protecting fat stores when food is scarce and other studies demonstrating the effects of treatment with leptin at doses that increase plasma levels to values found in overfed animals, we investigated whether leptin serves an adipostatic function within the normal range of free-feeding lean animals, i.e. within the very small range of endogenous plasma levels at which no leptin resistance occurs. For this purpose we applied recombinant leptin via mini-osmotic pumps to rats between 15 and 24 days of age and between 25 and 34 days of age and studied its dose-dependent effects on body mass and fat mass at plasma leptin concentrations extending down to the normal levels in lean animals. Using percentage change of fat mass (relative to that of saline-treated littermates) as the measure, a linear dose-response curve was found up to doses of 2 microg g(-1) day(-1), corresponding to plasma leptin concentrations between the normal physiological range and 50 ng ml(-1). In 15- to 24-day-old animals, analysis of the correlation (r = -0.89) between individual plasma concentrations and the corresponding leptin-induced changes of body fat content for a range extending down towards zero (i.e. towards the average fat content of the controls) yielded a zero value of 3.1 ng ml(-1), which was within the 2-4 ng ml(-1) range of plasma leptin concentrations found in the control pups. Likewise, regression analysis for the data from the 25- to 34-day-old pups (r = -0.88), for which the control range was 1-3 ng ml(-1), yielded a zero value of 1.9 ng ml(-1). We conclude that normal plasma leptin levels represent an adipostatic signal. Steady-state levels of plasma leptin in free-feeding lean animals thus provide a signal not only for protecting sufficiency but also for limiting increases of body fat stores.