The induction of lipocalin-2 protein expression in vivo and in vitro

J Biol Chem. 2014 Feb 28;289(9):5960-9. doi: 10.1074/jbc.M113.532234. Epub 2014 Jan 5.


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, IFNγ and TNFα, in cultured murine and human adipocytes. In these studies, we demonstrated that IFNγ and TNFα 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 IFNγ-induced lipocalin-2 expression in murine adipocytes. Similarly, knockdown of p65 in adipocytes demonstrated the necessity of the NF-κB signaling pathway for TNFα-mediated effects on LCN2. Activation of ERKs by IFNγ and TNFα also affected STAT1 and NF-κB signaling through modulation of serine phosphorylation. ERK activation-induced serine phosphorylation of both STAT1 and p65 mediated the additive effects of IFNγ and TNFα on LCN2 expression. Our results suggest that these same mechanisms occur in humans as we 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.

Keywords: Adipocyte; Adipose Tissue; ERK; Interferon; NF-κB; STAT; Tumor Necrosis Factor (TNF).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3-L1 Cells
  • Acute-Phase Proteins / biosynthesis*
  • Acute-Phase Proteins / genetics
  • Adipocytes / cytology
  • Adipocytes / metabolism*
  • Adipose Tissue, White / cytology
  • Adipose Tissue, White / metabolism*
  • Animals
  • Gene Expression Regulation / physiology*
  • Gene Knockdown Techniques
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Lipocalin-2
  • Lipocalins / biosynthesis*
  • Lipocalins / genetics
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Oncogene Proteins / biosynthesis*
  • Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / genetics
  • Response Elements / physiology*
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Acute-Phase Proteins
  • IFNG protein, human
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • RELA protein, human
  • Rela protein, mouse
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Stat1 protein, mouse
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Lcn2 protein, mouse
  • Interferon-gamma