Investigating the Role of the PGF2 Alpha/Calcineurin-Signaling Pathway in the Regulation of Adipogenesis

<p>Prostaglandin F2&alpha; (PGF2&alpha;) is a potent physiological inhibitor of adipocyte differentiation. In previous studies, we demonstrated that PGF2&alpha; inhibits adipogenesis via activation of the calcium-regulated protein phosphatase, calcineurin. In this current study, we have now extended these findings to identify the IL-11 cytokine and the Nurr1 orphan nuclear hormone receptor as functionally important downstream transcriptional targets of the PGF2&alpha;/calcineurin-pathway involved in the inhibition of adipocyte differentiation. In the case of IL-11, we show that this cytokine acts in an autocrine fashion to inhibit adipogenesis via the essential actions of the gp130 cytokine co-receptor signaling subunit. Further, by using a well-characterized panel of chimeric gp130 receptor mutants, we demonstrate that the activation of gp130-dependent signaling is sufficient to inhibit adipogenesis, and that the activation of the STAT1 transcription factor is necessary for this effect. Conversely, we find that the depletion of endogenous STAT1 rescues adipogenesis from the anti-adipogenic effects of both IL-11 and PGF2&alpha;. Taken together, these data provide evidence of a role for an autocrine IL-11/gp130/STAT1-dependent signaling cascade in mediating the inhibitory effects of the PGF2&alpha;/calcineurin-signaling pathway on adipogenesis. In the case of Nurr1, using a dominant-negative approach, we provide evidence that Nurr1 is also involved in mediating the inhibitory effects of PGF2&alpha; on adipogenesis. Further, using a panel of selective Nurr1 mutants, we demonstrate that the anti-adipogenic effects of Nurr1 are dependent upon its ability to directly bind DNA, but not its ability to heterodimerize with its nuclear partner protein, RXR. Additional experiments reveal that the PGF2&alpha;/calcineurin-signaling pathway induces expression of Nurr1 via the action of the CREB transcription factor, and more specifically, its association with members of the calcineurin-sensitive, CREB-regulated transcriptional co-activator (CRTC) family of proteins. Taken together, these results provide evidence that, in addition to IL-11, the CRTC/CREB/Nurr1-dependent signaling cascade also plays a role in mediating the inhibitory effects of the PGF2&alpha;/calcineurin-signaling pathway on adipogenesis. Collectively, these studies identify two parallel pathways that act in concert downstream of calcineurin to mediate the inhibitory effect of PGF2&alpha; on adipocyte differentiation, thereby affording significant new insights into the molecular mechanisms by which the PGF2&alpha;/calcineurin-signaling pathway inhibits the adipogenic process.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmacology and Experimental Therapeutics

Year dc:date.available

2014

Author dc:creator

• Annamalai, Damodaran

• Molecular Biology

Repository record dc:identifier

https://ecommons.luc.edu/luc_diss/885

OAI identifier oai:identifier

oai:ecommons.luc.edu:luc_diss-1884