Leptin is a 16 kDa peptide predominantly produced by adipocytes. Leptin and its receptor are known to be involved in the regulation of energy balance. The data from animal studies as well as our own observations of leptin overflow from the brain suggest that the central nervous system is a site of leptin synthesis. Using simultaneous arterio-venous blood sampling we here confirm that leptin is released from the brain into the internal jugular vein, and that release is greater in overweight men and in females compared to lean men, 467.3 ng/min+/-160.4 and 1426 ng/min+/-769.3 vs 80.0 ng/min+/-29.3, respectively (P<0.05). Furthermore, we have examined the gene expression of leptin and its receptor isoforms by reverse transcription-polymerase chain reaction (RT-PCR) in human cadaver hypothalami across a broad range of adiposity. Leptin gene expression was detected in a number of donors; the presence of detectable leptin mRNA was related to the mode of death rather than BMI or gender. We have also demonstrated gene expression of the three leptin receptor isoforms in the human hypothalamus. No relation was observed between the levels of hypothalamic expression of the long signaling form of the leptin receptor and BMI. In summary, this study indicates that it is very difficult to explain human obesity on the basis of central nervous system "leptin resistance", in that leptin is released in the brain, and at a higher level in the obese, and brain leptin receptor gene expression is not impaired in obesity.