Effects of continuous lumbar intrathecal infusion of leptin in rats on weight regulation.

Intracranial leptin alters food consumption and body weight. To systematically characterize the effects of extended continuous spinal intrathecal delivery on such regulation, female rats received continuous lumbar spinal infusion (14 days) through catheters connected to osmotic minipumps of a vehicle or one of several doses of recombinant murine leptin (0.03-10 microg/day). The following observations were made. (1) Leptin resulted in a dose-dependent suppression in body weight and food consumption at doses above 0.3 microg/day. (2) Food consumption was initially reduced. Weight fell for 7 days and then plateaued at a level proportional to dose. (3) The ratio of food consumed to body weight was constant for control animals across the study. Leptin-infused rats slowed the initial fall in weight by increasing food consumption, such that the food to body weight ratio returned to that of control values. Rats were thus regulating food consumption to sustain body weight as defined by leptin dose. (4) On day 14, cisternal cerebrospinal fluid was obtained and leptin measured. Concentrations covaried in a log linear fashion with infusion dose. Body weight and food consumption covaried similarly with cisternal leptin concentrations across dose groups. Our data suggest that steady state infusions of leptin induce a degree of appetite suppression that leads to a steady state level of body weight loss and not simply to a simple block of consumatory behavior. The unexpected potency of the observed effects of intrathecal leptin relative to doses that are required after i.c.v. delivery suggests that at least a portion of the effects of intrathecal leptin may reflect a medullary action. The observed correlation of cisternal leptin levels with the behavioral effects is also consistent with a reliable distribution of the infused leptin to target supraspinal sites.