title: Cross-talk between interferon-γ and hedgehog signaling regulates adipogenesis.
abstract: 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.
  
  
  METHODS
  We used Hh reporter cells, cell lines, and primary adipocyte differentiation models to explore costimulation of IFN-γ and Hh signaling. Genetic dissection using Ifngr1(-/-) and Stat1(-/-) 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(-/-) and Stat1(-/-) 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.
authors.affiliation: Department of Laboratory Medicine, Medical University Vienna,Vienna, Austria.
authors.forename: Jelena
authors.initials: J
authors.lastname: Todoric
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.forename: Alexander
authors.initials: A
authors.lastname: Jais
authors.forename: Nicole
authors.initials: N
authors.lastname: Boucheron
authors.forename: Martina
authors.initials: M
authors.lastname: Bayer
authors.forename: Sabine
authors.initials: S
authors.lastname: Amann
authors.forename: Josefine
authors.initials: J
authors.lastname: Lindroos
authors.forename: Raffaele
authors.initials: R
authors.lastname: Teperino
authors.forename: Gerhard
authors.initials: G
authors.lastname: Prager
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Wilfried
authors.initials: W
authors.lastname: Ellmeier
authors.forename: Franz
authors.initials: F
authors.lastname: Krempler
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Oswald
authors.initials: O
authors.lastname: Wagner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Patsch
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000096743:Interferon gamma Receptor
chemical_list: D053823:Hedgehog Proteins; D007371:Interferon-gamma; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse