ObjectiveThe neuroprotective effects of liraglutide (200 μg/kg, twice daily, subcutaneous administration) in the hypothalamic arcuate nucleus (ARC) of diet‐induced obese mice were investigated.MethodsC57BL/6 mice were separated into groups: standard chow treated with vehicle or liraglutide and the respective liraglutide pair‐fed group; high‐fat diet treated with vehicle or liraglutide and the respective pair‐fed group. Body mass (BM) evolution, carbohydrate metabolism, leptin resistance, proteins involved in energetic balance, apoptosis, and microglia in the ARC were studied.ResultsObese animals showed glucose intolerance, resistance to insulin and to anorexigenic effect of leptin, and microgliosis accompanied by elevated Bax/Bcl2 ratio in the ARC. Liraglutide improved the carbohydrate metabolism, BM loss, and the activation of pro‐opiomelanocortin (POMC) and cocaine and amphetamine‐regulated transcript (CART) in the ARC. The liraglutide enhanced leptin sensitivity and diminished the microgliosis with decrease in Bax/Bcl2 ratio.ConclusionsLiraglutide activates central anorexigenic pathways, thereby diminishing the energy intake of obese mice and improving the metabolic parameters related to obesity. Liraglutide is a relevant neuroprotective agent, which can decrease the microgliosis and stimulate the anti‐apoptotic pathway, a significant effect in the treatment of obesity and its comorbidities. Some benefits of liraglutide are independent of the BM loss, which usually accompanies the drug administration.