Leptin resistance in mice with diet-induced obesity (DIO) involves two distinct mechanisms. The study shows that high-fat diets lead to reduced leptin signaling in the hypothalamus, even though leptin can still activate signaling when administered directly into the brain (icv route). This suggests that peripheral leptin cannot reach its target sites in the hypothalamus, likely due to a defect in the blood-brain barrier. Additionally, there is an intracellular signaling defect in leptin-responsive neurons, which impairs STAT3 activation. These findings indicate that leptin resistance in DIO mice is not a single phenomenon but results from two independent defects: one related to access of leptin to the hypothalamus and another involving intracellular signaling pathways. The study highlights the complexity of leptin signaling in obesity and suggests that therapies targeting the blood-brain barrier or intracellular signaling pathways may be effective in treating leptin resistance.Leptin resistance in mice with diet-induced obesity (DIO) involves two distinct mechanisms. The study shows that high-fat diets lead to reduced leptin signaling in the hypothalamus, even though leptin can still activate signaling when administered directly into the brain (icv route). This suggests that peripheral leptin cannot reach its target sites in the hypothalamus, likely due to a defect in the blood-brain barrier. Additionally, there is an intracellular signaling defect in leptin-responsive neurons, which impairs STAT3 activation. These findings indicate that leptin resistance in DIO mice is not a single phenomenon but results from two independent defects: one related to access of leptin to the hypothalamus and another involving intracellular signaling pathways. The study highlights the complexity of leptin signaling in obesity and suggests that therapies targeting the blood-brain barrier or intracellular signaling pathways may be effective in treating leptin resistance.