Leptin and its neuronal targets, which produce proopiomelanocortin (POMC) and agouti-related protein (AgRP), regulate energy balance. This study characterized leptin, POMC, and AgRP in the cerebrospinal fluid (CSF) of 47 healthy human subjects, 23 lean and 24 overweight/ obese (OW/OB), as related to BMI, adiposity, plasma leptin, soluble leptin receptor (s-OB-R), and insulin. POMC was measured since the POMC prohormone is the predominant POMC peptide in CSF and correlates with hypothalamic POMC in rodents. Plasma AgRP was similarly characterized. CSF leptin was 83-fold lower than in plasma and correlated strongly with BMI, body fat, and insulin. The relative amount of leptin transported into CSF declined with increasing BMI, ranging from 4.5 to 0.52%, consistent with a saturable transport mechanism. CSF sOB-R was 78-fold lower than in plasma and correlated negatively with plasma and CSF leptin. CSF POMC was higher in lean vs. OW/OB subjects (P Ͻ 0.001) and correlated negatively with CSF leptin (r ϭ Ϫ0.60, P Ͻ 0.001) and with plasma leptin, insulin, BMI, and adiposity. CSF AgRP was not different in lean vs. OW/OB; however, plasma AgRP was higher in lean subjects (P ϭ 0.001) and correlated negatively with BMI, adiposity, leptin, insulin, and HOMA (P Ͻ 0.005). Thus, CSF measurements may provide useful biomarkers for brain leptin and POMC activity. The striking negative correlation between CSF leptin and POMC could be secondary to leptin resistance and/or neuronal changes associated with obesity but may also indicate that POMC plays a primary role in regulating body weight and adiposity. The role of plasma AgRP as a neuroendocrine biomarker deserves further study.proopiomelanocortin; agouti-related protein; leptin; cerebrospinal fluid THE ADIPOCYTE-DERIVED HORMONE leptin communicates levels of energy stores to key brain regions and elicits a host of neuronal responses that regulate energy balance (6,14). Leptin enters the brain by a saturable transport mechanism that involves, at least in part, a short isoform (Ob-Ra) of the leptin receptor found in the choroid plexus and cerebral microvessels (1, 9). Another circulating leptin receptor isoform, the soluble leptin receptor (sOB-R or Ob-Re), can also impact leptin transport into the brain. sOB-R may be derived from ectodomain shedding of the long form of the leptin receptor OB-Rb that is essential for leptin signaling (7). The physiological role of sOB-R is not yet completely understood. There is evidence that sOB-R functions as a leptin-binding protein that can inhibit leptin transport into brain but can also delay leptin clearance from the circulation (11, 33). High levels of sOB-R can block leptin's actions (26), but sOB-R overexpression results in a lean phenotype in mice (16). In humans, plasma sOB-R levels correlate negatively with BMI and increase with fasting(4, 34).The hypothalamic melanocortin system plays a critical role in responding to leptin, and disruption of this system at multiple levels causes obesity in humans and animals. This system consists of p...