Cross-Talk Between Interferon-7 and Hedgehog Signaling Regulates Adipogenesis

摘要

OBJECTIVE—T cells and level of the cytokine interferon-7 (IFN-7) 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-7 and Hh signaling cross-talk, we examined their potential interaction in the context of adipogenesis. RESEARCH DESIGN AND METHODS—We used Hh reporter cells, cell lines, and primary adipocyte differentiation models to explore costimulation of IFN-7 and Hh signaling. Genetic dissection using Ifngrl~(-/-) and Statl~(-/-) mouse embryonic fibroblasts, and ultimately, anti-IFN-γ neutralization and expression profiling in obese mice and humans, respectively, were used to place the findings into the in vivo context. RESULTS—T-cell supernatants directly inhibited hedgehog signaling in reporter and 3T3-L1 cells. Intriguingly, using blocking antibodies, Ifngrl~(-/-) and Statl~(-/-) cells, and simultaneous activation of Hh and IFN-γ signaling, we showed that IFN-γ 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-7 depletion in mice identify the system as intact in adipose tissue in vivo. CONCLUSIONS—These results identify a novel antagonistic cross-talk between IFN-7 and Hh signaling in white adipose tissue and demonstrate IFN-7 as a potent inhibitor of Hh signaling. Diabetes 60:1668-1676, 2011