Objective <p>Obesity-induced inflammation in the hypothalamus disrupts the function of neurons that regulate appetite, particularly proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons in the arcuate nucleus (ARC). Although Liraglutide, a GLP-1 analogue, exhibits neuroprotective properties, the underlying molecular mechanisms are unclear. In this study, we investigated whether Liraglutide protects hypothalamic neurons via the PI3K/AKT/Foxo1 pathway.</p> Methods <p>Male SD rats (<i>n</i> = 40) were fed a high-fat (HFD) or normal-fat (NFD) diet for 12 weeks. The obese rats on the HFD received Liraglutide (200&#xa0;µg/kg/day, HL) or saline (HS), while the NFD controls received Liraglutide (NL) or saline (NS) for 6 weeks. Metabolic parameters, neuronal ultrastructure (TEM/Nissl staining), apoptosis (TUNEL assay) and biomarkers of the PI3K/AKT/Foxo1 pathway were analysed using immunofluorescence, RT-PCR and Western blotting.</p> Results <p>The HFD group showed more weight gain, higher fasting blood glucose levels, and insulin resistance compared to the NFD. Rats on the HFD showed neuronal damage (reduced Nissl bodies and nuclear fragmentation) and apoptosis (more TUNEL-positive cells) in the ARC. Liraglutide reversed these effects. The HL group showed lower levels of apoptosis compared to the HS group. At the same time, there was an increase in the activity of the POMC and a decrease in the NPY/AgRP (<i>p</i> &lt; 0.05). Mechanistically, Liraglutide activates the PI3K/AKT pathway, reduces Foxo1 expression and balances Bcl-2/Bax apoptotic regulators.</p> Conclusion <p>Liraglutide improves hypothalamic neuronal apoptosis in obesity by activating the PI3K/AKT signalling pathway, which reduces Foxo1-mediated apoptosis and brings the balance of POMC and NPY neurons back to normal. These findings explain a key mechanism of Liraglutide’s anti-obesity effects and demonstrate its potential for neuroprotection.</p>