The induction of lipocalin-2 expression in vivo and in vitro [Metabolism]

January 5th, 2014 by Zhao, P., Elks, C. M., Stephens, J. M.

Lipocalin-2 (LCN2) is secreted from adipocytes and its expression is up-regulated in obese and diabetic mice and humans. LCN2 expression and secretion has been shown to be induced by two pro-inflammatory cytokines, IFNγ and TNFα, in cultured murine and human adipocytes. In these studies, we demonstrate that IFNγ and TNFα induce LCN2 expression and secretion in vivo. Although, we observe a strong induction of LCN2 expression and secretion from white adipose tissue depots, the induction of LCN2 varies among different insulin sensitive tissues. Knock down experiments also demonstrate that STAT1 is required for IFNγ-induced lipocalin-2 expression in murine adipocytes. Similarly, adipocytes with substantially reduced levels of p65 demonstrate that the NF-κB signaling pathway is necessary for the TNFα-mediated effects on LCN2. Activation of ERKs by IFNγ and TNFα also affects STAT1 and NF-κB signaling through modulation of serine phosphorylation. ERK activation-induced serine phosphorylation of both STAT1 and p65 mediate the additive effects of IFNγ and TNFα; on LCN2 expression. Our results suggest that these same mechanisms occur in humans as we have observed STAT1 and NF-κB 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.