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

Abstract

OBJECTIVET 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 METHODSWe 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.RESULTST-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.CONCLUSIONSThese 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.

Hürthle Cells Predict Hypothyroidism in Interferon-γ Transgenic Mice of Different Genetic Backgrounds

“…The finding is in keeping with recent studies showing that IFN␥ promotes adipogenesis and adipocyte differentiation via inhibition of hedgehog signaling (27). Adipocytes were overall more abundant in the thyroid of IFN␥ transgenic mice than in those of wild-type controls but were markedly influenced by the genetic background.…”

“…This explanation seems unlikely, however, because adipocytes were found also in IFN␥ transgenic that had mild thyroid disruption. We favor a scenario in which adipocytes are recruited to the thyroid as a direct consequence of IFN␥, in keeping with the stimulatory role IFN␥ has on adipogenesis (27). Recent studies have highlighted a crosstalk between adipocytes and macrophages.…”

Elevated Serum IL-6, IL-8, MCP-1, CRP, and IFN-γ Levels in 10- to 11-Year-Old Boys with Increased BMI

“…IFN-γ) may be regarded as a mechanism contributing to inflammation in obesity. Todoric et al [2] proposed a possible mechanism by which IFN-γ may be involved in the pathogenesis of obesity. They demonstrated that IFN-γ is a potent inhibitor of Hedgehog signaling: a inhibitor in white adipocyte differentiation.…”

“…However, the exact mechanisms of how these changes lead to the accumulation of fat mass are not yet fully understood. Recent studies have shown that inflammation also has a role in the pathogenesis of obesity [2]. Different inflammatory markers, such as IL-6, IL-1β, CRP, and TNF-α, are increased in childhood obesity [3,4,5,6,7].…”

The role of JAK–STAT signaling in adipose tissue function

“…Shh signaling specifically blocks adipogenesis in white, but not brown adipose tissue [69,92]. IFNγ inhibits fat cell differentiation in the absence of Shh signaling [30,40,96]. However, when the Shh pathway is activated in various preadipocyte model systems, IFNγ blocks Shh signaling and rescues adipogenesis via a JAK-STAT1-dependent mechanism [96].…”