This study investigates the molecular basis of leptin resistance in mice with diet-induced obesity (DIO). The researchers examined the ability of leptin to activate STAT3 signaling in the hypothalamus of C57BL/6J mice fed either a low-fat or high-fat diet. They found that while leptin could activate STAT3 signaling when administered intraperitoneally (ip) or intracerebroventricularly (icv) in mice on a low-fat diet, it failed to do so in mice on a high-fat diet after 15 weeks. However, icv leptin administration was still effective in activating STAT3 signaling in high-fat diet mice, suggesting a defect in leptin access to the hypothalamus. Additionally, the study identified a signaling defect upstream of STAT3 activation in leptin-responsive hypothalamic neurons, which may involve factors such as SOCS-3 and PIAS-3. These findings highlight two independent causes of leptin resistance in DIO: a defect in leptin access and a signaling defect in hypothalamic neurons.This study investigates the molecular basis of leptin resistance in mice with diet-induced obesity (DIO). The researchers examined the ability of leptin to activate STAT3 signaling in the hypothalamus of C57BL/6J mice fed either a low-fat or high-fat diet. They found that while leptin could activate STAT3 signaling when administered intraperitoneally (ip) or intracerebroventricularly (icv) in mice on a low-fat diet, it failed to do so in mice on a high-fat diet after 15 weeks. However, icv leptin administration was still effective in activating STAT3 signaling in high-fat diet mice, suggesting a defect in leptin access to the hypothalamus. Additionally, the study identified a signaling defect upstream of STAT3 activation in leptin-responsive hypothalamic neurons, which may involve factors such as SOCS-3 and PIAS-3. These findings highlight two independent causes of leptin resistance in DIO: a defect in leptin access and a signaling defect in hypothalamic neurons.