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OBJECTIVE--T cells and level of the cytokine interferon-γ (IFN-γ) 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-γ 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 fines, and primary adipocyte differentiation models to explore costimulation of IFN-γ and Hh signaling. Genetic dissection using [Ifngr1.sup.-/-] and [Stat1.sup.-/-] 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, [Ifngr1.sup.-/-] and [Stat1.sup.-/-] 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-γ depletion in mice identify the system as intact in adipose tissue in vivo. CONCLUSIONS--These results identify a novel antagonistic cross-talk between IFN-γ and Hh signaling in white adipose tissue and demonstrate IFN-γ as a potent inhibitor of Hh signaling., The World Health Organization (WHO) currently estimates that more than 1 billion individuals worldwide are overweight. Almost one-third of these individuals are clinically obese, markedly raising their chances of cardiovascular [...]