AIM: To clarify whether centrally delivered leptin can access the circulation and to determine to what extent the effects of i.c.v. h-leptin and m-leptin on body weight and plasma corticosterone are due to reduced food intake. METHODS: Male lean Zucker rats were infused i.c.v. with recombinant m-leptin or h-leptin (42 microg/day) for 7 days. Terminal plasma leptin levels were measured using selective r-leptin, m-leptin and h-leptin RIA. Plasma h-leptin and corticosterone levels were determined on days 0, 2, 4 and 6 of h-leptin infusion. Interscapular brown adipose tissue weight and UCP-1 mRNA expression (an indicator of thermogenic capacity) were also measured. RESULTS: The terminal plasma leptin level was elevated (from 2.2 +/- 0.4 to 42.7 +/- 20.2 ng/ml) in the h-leptin-treated lean rats to levels similar to those in vehicle i.c.v. infused fa/fa rats (72.2 +/- 4.7 ng/ml), but this was only detectable when the h-leptin radioimmunoabsorbent assay (RIA) was used. Further, both m-leptin and h-leptin infusions in lean rats elevated terminal plasma corticosterone (352 +/- 37 and 389 +/- 55 ng/ml, respectively) to levels similar to those in i.c.v. rats (386 +/- 62 ng/ml), whereas diet-restriction by pair-feeding, with the h-leptin group, in lean rats had no effect (207 +/- 45 ng/ml). The increase in plasma corticosterone level coincided with the maximum hypophagic effects of leptin and preceded the appearance and sustained elevation of exogenous human leptin in the circulation. Both m-leptin and h-leptin i.c.v. infusion reduced body weight gain (3% and 4%, respectively, compared to pair-fed group) and increased UCP-1 expression (11-fold and 16-fold, respectively) in lean rats. However, h-leptin elicited an earlier effect than m-leptin on body weight, manifested as an earlier reduction in food intake and greater increase in UCP-1 expression. h-Leptin also elicited a greater reduction in body weight gain than did pair-feeding. CONCLUSIONS: Intracerebroventricular-infused m-leptin or h-leptin was detected in the circulation. Furthermore, m-leptin and h-leptin elevated plasma corticosterone levels and h-leptin caused some weight loss in lean rats independently of its suppression of food intake. The elevation of corticosterone levels in the lean rats may be a mechanism whereby they resist excessive weight loss in response to leptin.