Objective  To investigate the effects of leptin on hypothalamic neuron activity and lipid metabolism in adipose tissue of obese mice. Methods 10 leptin-deficient obese (ob/ob) mice with homozygous mutation of leptin gene and 10 wild-type（WT）mice born in the same litter were randomly divided into control group and leptin treatment group. The activity of pro-opiomelanocortin(POMC) neurons and tyrosine hydroxylase(TH⁺) neurons, the morphological changes of adipose tissue and the expression of lipid-related genes were analyzed by immunofluorescent staining, HE staining and Real-time PCR. Results  Compared with the WT mice, the ob/ob mice showed decreased activity of POMC neurons and TH⁺ neurons and larger cell diameter in adipose tissue and liver tissue. In addition, the expressions of heat-related genes uncoupling protein 1(UCP1), cytochrome c oxidase subunit 8B(Cox8b) and cell death-inducing DNA fragmentation factor, alpha subunit-like effector A(Cidea) in subcutaneous white fat in ob/ob mice decreased significantly, and the expressions of lipid synthesis-related genes sterol regulatory element binding transcription factor 1(Srebp1) and fatty acid synthase(Fas) increased significantly. After treated with leptin, the activities of POMC and TH⁺ neurons were increased, and the cellular diameter and the degree of vacuolar degeneration were reduced in the adipose tissue and liver. Further analyses showed that the expressions of thermogenesis-related genes and lipolysis-related genes were increased, but expressions of lipid synthesis-related genes were reduced in brown adipose tissue. Conclusion  Leptin treatment could prevent the increasing of obesity in ob/ob mice, which is associated with increased lipolysis and reduced lipid synthesis through activation of hypothalamic POMC neurons and peripheral adipose tissue sympathetic nervous system