ACE is highly expressed by differentiated macrophages (MF), where its role is currently unclear. Since obesity is associated with increased infiltration of MF into adipose tissue, contributing to the development of insulin resistance, we determined whether adipocyte-conditioned medium (AM) affects ACE expression of MF and thus the cytokine profile/polarization. Human blood derived monocytes were differentiated into MF for 5 days. Pre- /Adipocytes were isolated from human donor material, cultured for 5 days/24 hours, and AM collected over 24 hours. Incubation of MF with AM resulted in a significant increase in ACE expression. The effect was not observed following incubation of MF with conditioned medium from preadipocytes or after extraction of lipids from AM, suggesting that a lipid factor mediates the crosstalk between the two cell types. mRNA expression of MHCII (major histocompatibility complex class II protein/HLA- DMB) increased in parallel to ACE expression in AM-treated MF, whereas expression of VEGF, TNF-a, MCP-1, IL-10 and COX-2 were decreased, reflecting M2 MF polarization. As a consequence MCP-1 reduction, medium from AM- treated MF promoted less monocyte migration than medium of solvent-treated MF. Interestingly, ACE- expression was also upregulated after treatment with classical inducers of M2 polarization (IL- 4, IL-13) and decreased in MF treated with M1 inducers (LPS, IFNg). The signaling pathway induced by AM in MF involves the AMP-activated protein kinase (AMPK), since incubation with AM increased AMPK-phosphorylation and AMPK- inhibition prevented the AM-mediated ACE- increase. These data demonstrate that mature adipocytes modulate the expression profile of MF by the release of lipids which initiate M2 MF polarization. The observed AMPK activation and ACE upregulation in this MF subset might provide a molecular link between the AMPK, which is implicated in whole body insulin sensitivity, and ACE inhibitors, which delaye the onset of type II diabetes.