Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology and Experimental Therapeutics

Abstract

Prostaglandin F2α (PGF2α) is a potent physiological inhibitor of adipocyte differentiation. In previous studies, we demonstrated that PGF2α 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 PGF2α/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 PGF2α. 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 PGF2α/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 PGF2α 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 PGF2α/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 PGF2α/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 PGF2α on adipocyte differentiation, thereby affording significant new insights into the molecular mechanisms by which the PGF2α/calcineurin-signaling pathway inhibits the adipogenic process.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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