Macrophage-secreted Factors Inhibit ZAG Expression and Secretion by Human Adipocytes

Zinc-alpha2-glycoprotein (ZAG), a novel adipokine, is downregulated in adipose tissue in obesity, a state characterized by increased adipose tissue macrophage infiltration and chronic low-grade inflammation. This study investigated whether macrophage-secreted factors and TNF-alpha, a major product of macrophages, modulate ZAG expression and secretion by human adipocytes. ZAG was produced primarily by adipocytes, and not by preadipocytes and macrophages. Incubation of preadipocytes with macrophage-conditioned medium for up to 12 days decreased ZAG mRNA and protein release, and the expression of adipogenic markers (PPARgamma and C/EBPalpha). Adipocytes treated with macrophage-conditioned medium for 24h displayed significant reductions in ZAG mRNA and release. Chronic TNF-alpha treatment let to significant decreases in ZAG expression and secretion, but marked upregulation of pro-inflammatory cytokines and chemokines (IL-6, leptin, IL-8, MCP-1 and RANTES) in adipocytes. These findings suggest that macrophage-associated inflammation may play a significant role in the downregulation of ZAG in adipose tissue in obesity.