It has been recently demonstrated that inflammatory responses in the brain are associated with a number of metabolic diseases, including high fat diet-induced obesity. Still, the precise cellular sources and targets during the inflammatory processes in the brain are poorly understood. Microglia cells, the main immune resident cells in the brain have been shown to be activated in the arcuate nucleus (ARC) of high fat diet-induced obesity, producing pro-inflammatory mediators. However, the downstream consequences on ARC neuronal activity have not yet been investigated. In this study, we evaluated the effects of microglia TLR4 (toll-like receptor 4) activation (by LPS, lipopolysaccharide) on NPY (hypothalamic neuropeptide Y) and POMC (pro-opiomelanocortin) ARC neurons firing activity. Conventional whole-cell patch-clamp recordings in brain slices were obtained from ARC neurons (lateral-POMC neurons and medial-NPY neurons portion of ARC), or from NPY neurons at ARC, obtained from control rats and eGFP-NPY transgenic mice, respectively. Current-clamp measurements of mean membrane potential and firing rate were assessed in period before, during and after bath-applied LPS (10ug/ml, an agonist of TLR4) and minocycline (100uM, an agent that inhibits activated microglia). All values are expressed as means ± SEM (n=cells). Results were compared using paired t tests or ANOVA. Differences were considered statistically significant at a P<0.05. In the current study, we report that microglial activation with bath-applied LPS induced an increase in the firing activity in most 56% of neurons at lateral ARC, which was underlied by membrane depolarization (P<0.05, n=16). These effects were not change when microglia cell were inhibited (58%, n=19). On the other hand, LPS induced a decrease in the firing discharge in most 53% of neurons at medial ARC, which was underlied by membrane hyperpolarization (P<0.05, n=15). Moreover, the inhibition of activated microglia cell reverts the effects of LPS showing increase in the firing activity in most 48% of neurons at medial ARC, which was underlied by membrane depolarization (P<0.05, n=23 cells). Similar results were observed in 77% of eGFP-NPY neurons showed a decrease in the firing activity (n=18). In the majority of these cases, LPS effects on NPY neurons were prevented by the microglia inhibitor minocycline (33%, n=9). These results indicate that activation of TLR4 by LPS induced contrasting effects on ARC neuronal activity. Thus, while TLR4 activation inhibited NPY neuronal activity, likely via activation of microglia cells, an excitatory effects was observed in putative POMC neurons, which was independent on microglia activation. These contrasting effects mediated by TLR4 activation would contribute to an overall anorexigenic effect during an inflammatory process.