Hyperleptinemia of pregnancy associated with the appearance of a circulating form of the leptin receptor

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 similar to 3 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.