The growing world-wide obesity epidemic is frequently linked to hyperlipidemia, inflammation, and insulin resistance leading to increased risk of diabetes and cardiovascular disease. Macrophages have been shown to infiltrate white adipose tissue (WAT) in obese mice and humans promoting inflammatory cytokine secretion and insulin resistance. As the adipokine leptin is secreted from WAT in direct proportion to adipose tissue mass, we hypothesized that leptin itself could act as a macrophage chemoattractant. This hypothesis was tested both in vitro using the Boyden chamber migration assay as well as in vivo. Leptin induced THP-1 monocyte migration at doses ranging from 1 pg/ml to 100 ng/ml, with maximal effects at 1 ng/ml (P<0.05 compared to control). Addition of equivalent concentrations of leptin to the top and bottom chamber completely inhibited THP-1 migration, providing evidence that leptin acts as a chemoattractant rather than a chemokinetic. Inhibition of PI3K, ERK1/2, and p38 MAPK completely blocked leptin- and MCP-l-induced THP-l cell migration. Primary peritoneal macrophages also migrate maximally to 1 ng/ml leptin, an effect which requires leptin receptor expression. To determine whether leptin-induced monocyte migration is a physiologically relevant mediator of adipose tissue macrophage accumulation, we performed bone marrow transplantation (BMT). Donor mice were either wild type (LepR[sup +/+) or leptin receptor deficient (LepR[sup db/db]), and all donors and recipients were on the LDLR deficient background. Twenty-four weeks post-BMT, mice were sacrificed. There were no differences between the two recipient groups in body weight, plasma lipid levels, glucose, insulin, or leptin levels. Mice receiving LepR[sup +/+] marrow showed a significant increase in WAT macrophage content as measured by increased WAT RNA levels of the macrophage markers CD68 and Mac-1 (P<0.05), and the inflammatory markers IL-6 and MCP-1. Taken together, these data demonstrate that leptin is a potent chemoattractant for monocyte/macrophages, and may contribute to the initiation of macrophage infiltration of WAT. [ABSTRACT FROM AUTHOR]