Suppression of Leptin Transport Into the Brain Contributes to Leptin Resistance During Pregnancy in the Mouse.

During pregnancy, when both food intake and circulating leptin concentrations increase, the brain becomes insensitive to leptin. The mechanism by which central leptin resistance during pregnancy emerges remains poorly understood. We investigated whether structural changes in the blood-brain barrier (BBB) or changes in carrier-mediated transport of leptin into the brain might contribute to pregnancy-induced leptin resistance. Immunohistochemical evaluation of the BBB at the level of the arcuate nucleus and median eminence in virgin, pregnant, and lactating mice was undertaken by labeling for tanycytes (vimentin), tight junction protein (zona occludens-1), and a marker of fenestrated endothelial capillaries (MECA-32). There were no changes in these BBB markers between virgin, pregnant or lactating mice. Transport of iodine 125-labeled leptin from the peripheral circulation into the brain was completely suppressed during pregnancy, however (days 14 through 16), compared with virgin and lactating (days 7 through 11) mice. This was accompanied by a suppression of leptin clearance from the blood in pregnant mice. We also investigated in virgin mice whether competition with other hormones for transport might contribute to suppression of leptin transport into the brain. Although leptin was able to compete with prolactin transport into the brain, prolactin did not compete with leptin transport. These data demonstrate that suppression of the transport of leptin into the brain during pregnancy, in the absence of structural changes in the BBB, is an important contributor to the insensitivity of the hypothalamus to leptin at this time.