A decrease of food intake has been shown after a single exposure to lipopolysaccharide (LPS). However, desensitization of hormone and behavioral responses to repeated exposure to endotoxin has been also described. Through hypothalamic leptin receptors (OB-Rb), circulating leptin signals the energy store to the brain and controls feeding behavior and energy balance, stimulating proopiomelanocortin (POMC) expression in the arcuate nucleus. POMC possesses anorexigenic effects mediated by melanocortin 4 receptor (MC4R) in the paraventricular nucleus. The aim of this study was to evaluate the effects of repeated administration of LPS at dark onset on plasma leptin levels, food intake and OB-Rb and MC4R mRNA expression in the hypothalamus. For these purposes, male Wistar rats (250-300g) received single or repeated injections of LPS (100 μg/Kg ip) or saline (0.15 M NaCl, 1ml/Kg), between 0400h-0500 PM, during six days. Food intake was determined after the last injection in previously fasted rats for 2h (n = 8). Another set of ad libitum fed rats was subjected to single or repeated injections of LPS or saline, and two or six hours after the last injection, truncal blood was collected by decapitation for measurement of plasma leptin levels by radioimmunoassay , and the brains were collected for determination of OB-Rb and MC4R mRNA expression by real time PCR (n = 7). Results were analyzed using ANOVA one way, followed by Student-Newman-Keuls and data are shown as mean±SEM. Single exposure to LPS decreased food intake and body weight gain (p<0.05), compared to control rats. Repeated injections of LPS induced no changes in food intake and body weight gain compared to controls. Plasma leptin levels increased (p<0.05) six hours after a single (6.1±0.7 ng/ml) dose of LPS, however there was no change after repeated (4.3±0.6 ng/ml) doses of LPS, compared to controls (4.0±0.3 ng/ml). There was an increase in the OB-Rb and MC4R mRNA expression in the paraventricular nucleus (p<0.05) two hours after a single exposure to LPS, compared to controls and repeated LPS-treated animals, with no changes in the OB-Rb mRNA expression in the arcuate nucleus. In conclusion, these data demonstrated that there is a desensitization of hypophagic effect in response to repeated exposure to endotoxin. Circulating leptin and OB-Rb and MC4R in the hypothalamus are likely to be involved in the control of food intake during endotoxemia.