Leptin is a hormone produced in adipose cells that regulates energy expenditure, food intake, and adiposity. In mice, we observed that circulating leptin levels increase 20 -40-fold during pregnancy. Pregnant ob/ob females had no detectable serum leptin, demonstrating that the heterozygous conceptus was not the source of the leptin. However, leptin RNA and protein levels in maternal adipose tissue were not elevated. The circulating leptin was in a high molecular weight complex, suggesting that the rise in leptin was due to expression of a binding protein. Indeed, quantitative assays of serum leptin binding capacity revealed a 40-fold increase, coincident with the rise in serum leptin. Leptin binding activity reached a capacity of 207 ؎ 15 nmol/liter of serum at day 18 of gestation, and half-maximal binding was observed with ϳ3 nM leptin. The binding protein was purified and partially sequenced, revealing sequence identity to the extracellular domain of the leptin receptor. We found that the placenta produces large amounts of the OB-Re isoform of leptin receptor mRNA, which encodes a soluble binding protein. Thus, the extreme hyperleptinemia of late pregnancy is attributable to binding of the leptin by a secreted form of the leptin receptor made by the placenta.Leptin, a hormone produced in adipose cells, is important in the regulation of metabolic efficiency, energy expenditure, food intake, and adiposity (1-3). It serves as a signal reporting the degree of adiposity: circulating leptin levels correlate best with the amount of body fat (4, 5). Mice lacking a functional leptin (formerly ob or obese) gene become massively obese and develop diabetes mellitus due to overeating and decreased metabolic expenditure (6). These mice are also hypogonadal and hypercorticosteronemic, presumably on a hypothalamic basis. Leptin treatment of ob/ob (lep ob /lep ob ) mice reverses all of these abnormalities, and in normal mice it causes decreased food intake, increased energy expenditure, weight loss, and precocious sexual maturity (7-11). Although much studied for its role in regulation of adiposity, leptin is probably of even greater importance in the metabolic adaptation to inadequate food intake (12).Metabolism during pregnancy is quite different from metabolism in the nongravid state. It is altered to provide rapid growth of the fetus and placenta and to prepare the mother for nursing. Some species, including humans and mice, accumulate maternal fat during gestation, and then use it during lactation (13, 14). The importance of leptin in the regulation of adiposity and energy metabolism led us to investigate the physiology of leptin during gestation in the mouse. In addition, the observation that leptin RNA is made by the human placenta (15, 16) suggested a role for leptin during pregnancy. To our surprise, we observed that, although mice have a profound hyperleptinemia in the third trimester of gestation, the murine placenta does not make leptin. There is, however, a massive increase in a circulating leptin-binding protein ...