Objective Neuroinflammation is a phenotype of leptin receptor (LEPR) mutated mice (db / db) and raises the question of whether LEPR is involved in microglial activation. To examine the function of LEPR on microglia cells, microglial activation was comparatively analyzed in LEPR^{+ /+} and LEPR^-/- rats. Methods RT-PCR, Western blot, immunohistochemistry, and immunofluorescence were used to examine microglia morphology, inflammatory factor secretion, and sensitivity to lipopolysaccharide ( LPS) treatment in vitro and in vivo. Results First, LEPR was expressed in microglia from LEPR^{+ /+} rats, while LEPR protein was completely deleted in microglia from LEPR^-/- rats. LEPR deletion enhanced sensitivity to LPS treatment and reduced survival rate of LEPR^-/- rats by 75%. Activated microglia were significantly increased in brain tissue of LEPR^-/- rats compared with LEPR^{+ /+} rats. LEPR deletion also increased the expression of inflammatory cytokines including interleukin ( IL) -6, inducible nitric oxide synthase, and Interleu bin-1β (IL-1β), and enhanced phagocytotic ability. Phosphatidylinositol-3-kinase (PI3K) / AKT phosphorylation was significantly increased in microglia from LEPR^-/- rats compared with LEPR^{+ /+} rats, suggesting that activation of the PI3K/ AKT signal pathway could partly be the mechanism of microglia activation. Conclusions Deletion of LEPR in microglia induced its activation and suggests the involvement of neuroinflammation in rats. Our result also suggest that the LEPR/ leptin axis plays important roles in neuroinflammation through microglia.