Doctor of Philosophy (PhD)


Biological Sciences

Document Type



Chronic inflammation in adipose tissue has been demonstrated to play an important role in the pathogenesis of insulin resistance. The infiltration of immune cells results in a significant increase of pro-inflammatory cytokines in adipose tissue that substantially affects adipocyte function. Lipocalin-2 (LCN2) is an adipocyte-secreted cytokine whose expression and secretion has been shown to be induced in obesity and insulin resistance in mouse and man. However, the underlying mechanisms have not been explored. Our studies indicate that interferon-gamma (IFNã) and tumor necrosis factor-alpha (TNFá), two primary pro-inflammatory cytokines secreted from immune cells, can induce LCN2 expression and secretion from adipocytes both in vivo and in vitro. Mechanistic studies reveal that IFNã modulates LCN2 expression via STAT1 and ERKs signaling pathways, while NF-êB and ERKs pathways mediate the actions of TNFá on LCN2 expression. Inhibition of ERKs activation attenuates the induction of LCN2 without significant effects on either the nuclear translocation or DNA binding activity of STAT1 and NF-êB. Further experiments show that pharmacological ERKs inhibition disrupts the serine phosphorylation of STAT1 and NF-êB p65 subunits, and reduces transactivation activity of both of these transcription factors. Moreover, we identified several STAT1 and NF-êB binding sites in both the murine and human LCN2 promoters. Overall, these studies enhance our knowledge regarding the requirements and mechanisms used by pro-inflammatory cytokines to induce LCN2 expression.



Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Jacqueline M. Stephens