Depending on the stimulus, macrophages (MF) are able to differentiate either into a classically activated, pro-inflammatory M1-MF-type or into an alternatively activated, anti-inflammatory M2-MF-type, each is characterized by the expression of specific marker proteins. Since obesity is associated with the increased infiltration of MF into the expanding adipose tissue, we determined whether adipocytes release factors that modulate ACE expression and MF differentiation. Human monocytes were isolated from whole blood and differentiated into MF by incubation for seven days in medium containing 5% human serum. Preadipocytes and adipocytes were isolated from donor material of patients (lipoaspiration), maintained in culture for 5 days or 24 hours, respectively, and the adipocyte-conditioned medium (ACM) collected over 24 hours. Incubation of human MF with ACM resulted in a significant (P<0,001) increase in MF ACE expression within four hours. The latter effect was not observed following the incubation of MF with conditioned medium from preadipocytes or after the extraction of lipids from the ACM using ether. In contrast, boiling the ACM (10 min, 95 °C) was without any effect on the ACM-induced increase in ACE expression, suggesting that a lipid factor within the ACM mediates the upregulation of ACE. Lipids/free fatty acids are able to activate different signalling pathways in MF. Using specific pharmacological inhibitors we were able to show that activation of a non-classical PKC isoform mediates the ACM-induced ACE-expression in MF, and that other lipid-induced signalling pathways, including JNK/c-Jun, toll-like receptors and peroxisome proliferator-activated receptors were not involved. Furthermore, the involvement of S1P could also be excluded, as S1P-receptor antagonists failed to inhibit ACM-induced upregulation of ACE expression. Analysis of the expression of M1-(TNF-a, IL-6) and M2-MF marker proteins (IL-10) in ACM-treated MF revealed their differentiation to the M2-MF-type. These data demonstrate that mature adipocytes modulate the expression profile of MF by the release of lipid factors or "lipokines" which can affect MF differentiation and function. The induction of the anti-inflammatory M2-MF-phenotype by adipocyte-derived lipids might be essential for the angiogenesis that takes place within the growing adipose tissue.