Leptin reduces adiposity and exerts anti-steatotic effects on non-adipose tissues. However, the mechanisms underlying leptin effects on lipid metabolism in liver and white adipose tissue have not been fully clarified. Here, we have studied the effects of central leptin administration on key enzymes and transcription factors involved in lipid metabolism in liver and epididymal adipose tissue. Intracerebroventricular leptin infusion for 7 days did not change leptin plasma levels but decreased triacylglyceride content in liver, epididymal adipose tissue and plasma. In both tissues, this treatment markedly decreased the expression of key enzymes of the de novo fatty acid synthesis such as ACC, FAS and SCD-1, in parallel with a reduction in mRNA expression of SREBP-1c in liver and ChREBP in adipose tissue. Additionally, leptin also decreased PEPCK-C expression in adipose tissue, an enzyme involved in glyceroneogenesis in this tissue. Central leptin administration down regulates delta 6-desaturase expression in liver and adipose tissue, in parallel to the decrease of the expression of SREBP-1c in liver and PPAR in adipose tissue. Finally, leptin treatment, by regulating ATGL/HSL/DAGT1 expression, also established a new partitioning in the fatty acid-TAG cycling in adipose tissue, increasing lipolysis and probably the fatty acid efflux from this tissue, and favoring in parallel the fatty acid uptake and oxidation in the liver. These results suggest that leptin, acting at central level, exerts tissue-specific effects in limiting fat tissue mass and lipid accumulation in non-adipose tissues, preventing the development of obesity and type 2 diabetes.