Desensitization of hormone response and hypophagic effect to repeated exposure to endotoxin has been described. Leptin, produced by adipose tissue, reduces food intake and boosts energy expenditure via activation of JAK/STAT signaling pathway in hypothalamic neurons, via a phosphorylation of STAT-3, which in turn stimulates SOCS-3 (an intracellular molecule that triggers a negative feedback loop) gene expression in the arcuate nucleus (ARC). We evaluate the effects of exogenous leptin administration in rats under single or repeated exposure to LPS on food intake and p-STAT-3 expression in the ARC. Male Wistar rats (250-300g) received single or repeated injections of LPS (100μg/Kg ip) or saline (0.15M NaCl, 1ml/Kg), between 0400h-0500 PM, during 6 days. Two hours after the last injection,rats received intracerebroventricular (icv) injection of leptin (10μg) or vehicle (saline). The anaesthetic for cannulation was tribromoethanol (1ml/100g bw, i.p.). Food intake was determined during 24h (n=8). Another set of rats, subjected to the same protocol, were anaesthetized (as above) and transcardially perfused with 4% formaldehyde. After 20 minutes the brains were collected for p-STAT-3 immunolabeling by immunohistochemistry (n=6). A third set of rats were treated with single or repeated LPS and two hours after the brains were collected by decapitation for determination of SOCS-3 mRNA expression by real time PCR (n=7). ANOVA one or two way, followed by Student-Newman-Keuls, was used to analyze the data (mean±SEM). Single LPS decreased food intake and body weight(p<0.05), compared to control rats. In turn, repeated LPS did not change the food intake and body weight.Icv leptin reduced(p<0.05) the food intake and body weight in 6 saline treated rats, but no changes in these parameters were observed in animals under single or repeated LPS. We observed an enhancement(p<0.05) of p-STAT-3 expressing neurons in the ARC after a single LPS followed by vehicle treatment compared to control (64.5 ± 19.4 vs 31.1 ± 19.8), with no changes in p-STAT-3 in 6 LPS group(17.8 ± 16.9). Leptin treatment increased p-STAT3 positive neurons in the ARC of 6 saline rats(62.1 ± 25 vs 5.3 ± 30.6)compared to vehicle. There was no effect of leptin on p-STAT-3 expression in the 6 LPS group. Compared to controls, there was an increase in the SOCS-3 mRNA expression in the ARC (p<0.05)after a single LPS, with no changes in the SOCS-3 mRNA in the repeated LPS-treated rats. In conclusion, these data demonstrated a desensitization of hypophagic effect in response to repeated exposure to endotoxin. This effect is associated with an insensitivity to leptin in activating STAT-3, however SOCS-3 is unlikely to underlie this resistance to leptin signaling in the ARC in the endotoxin tolerance.