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

OBJECTIVE-T cells and level of the cytokine interferon-gamma (IFN-gamma) are increased in adipose tissue in obesity. Hedgehog (Fib) signaling has been shown to potently inhibit white adipocyte differentiation. In light of recent findings in neurons that IFN-gamma 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-gamma and Hh signaling. Genetic dissection using Ifngr1(-/-) and Stat1(-/-) mouse embryonic fibroblasts, and ultimately, anti-IFN-gamma 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, lingr1(-/-) and Stat1(-/-) cells, and simultaneous activation of Hh and IFN-gamma signaling, we showed that IFINT-gamma 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-y depletion in mice identify the system as intact in adipose tissue in vivo. CONCLUSIONS These results identify a novel antagonistic cross-talk between IFN-gamma and Hh signaling in white adipose tissue and demonstrate IFN-gamma as a potent inhibitor of Rh signaling. Diabetes 60:1668-1676, 2011