The Induction of Lipocalin-2 Protein Expression in Vivo and in Vitro

Background: Lipocalin-2 is induced in obesity/type 2 diabetes. Results: TNF and IFN induce LCN2 in vivo. STAT1 and NF-B are required for LCN2 induction and bind the human LCN2 promoter. Conclusion: An interplay between ERKs, STAT1, and NF-B signaling pathways mediates the IFN and TNF induction of LCN2. Significance: Cytokine modulation of LCN2 increases our understanding of gene regulation in obesity/type 2 diabetes. Lipocalin-2 (LCN2) is secreted from adipocytes, and its expression is up-regulated in obese and diabetic mice and humans. LCN2 expression and secretion have been shown to be induced by two proinflammatory cytokines, IFN and TNF, in cultured murine and human adipocytes. In these studies, we demonstrated that IFN and TNF induced LCN2 expression and secretion in vivo. Although we observed a strong induction of LCN2 expression and secretion from white adipose tissue (WAT) depots, the induction of LCN2 varied among different insulin-sensitive tissues. Knockdown experiments also demonstrated that STAT1 is required for IFN-induced lipocalin-2 expression in murine adipocytes. Similarly, knockdown of p65 in adipocytes demonstrated the necessity of the NF-B signaling pathway for TNF-mediated effects on LCN2. Activation of ERKs by IFN and TNF also affected STAT1 and NF-B signaling through modulation of serine phosphorylation. ERK activation-induced serine phosphorylation of both STAT1 and p65 mediated the additive effects of IFN and TNF on LCN2 expression. Our results suggest that these same mechanisms occur in humans as we observed STAT1 and NF-B binding to the human LCN2 promoter in chromatin immunoprecipitation assays performed in human fat cells. These studies substantially increase our knowledge regarding the requirements and mechanisms used by proinflammatory cytokines to induce LCN2 expression.