May 10th, 2011 
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T cells and level of the cytokine interferon- (IFN-) are increased in adipose tissue in obesity. Hedgehog (Hh) signaling has been shown to potently inhibit white adipocyte differentiation. In light of recent findings in neurons that IFN- and Hh signaling cross-talk, we examined their potential interaction in the context of adipogenesis.
We used Hh reporter cells, cell lines, and primary adipocyte differentiation models to explore costimulation of IFN- and Hh signaling. Genetic dissection using Ifngr1–/– and Stat1–/– mouse embryonic fibroblasts, and ultimately, anti–IFN- neutralization and expression profiling in obese mice and humans, respectively, were used to place the findings into the in vivo context.
T-cell supernatants directly inhibited hedgehog signaling in reporter and 3T3-L1 cells. Intriguingly, using blocking antibodies, Ifngr1–/– and Stat1–/– cells, and simultaneous activation of Hh and IFN- signaling, we showed that IFN- directly suppresses Hh stimulation, thus rescuing adipogenesis. We confirmed our findings using primary mouse and primary human (pre)adipocytes. Importantly, robust opposing signals for Hh and T-cell pathways in obese human adipose expression profiles and IFN- depletion in mice identify the system as intact in adipose tissue in vivo.
These results identify a novel antagonistic cross-talk between IFN- and Hh signaling in white adipose tissue and demonstrate IFN- as a potent inhibitor of Hh signaling.
Diabetes Journal publish ahead of print articles
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