Background: Due to its various associated co-morbidities, obesity remains a rapidly growing health threat worldwide, driven by a high-fat diet (HFD). Therefore, it is crucial to further elucidate the impact of HFD on adipose tissue (AT) expansion, adipogenesis, and pathogenesis of metabolic syndrome. HFD has been shown to drive inflammation and metabolic dysfunction through type I interferon (IFN) signaling, a viral response pathway in which IFN-α and IFN-β cytokines bind receptors IFNAR1 and IFNAR2 to induce its gene signature. Moreover, obesity has been linked to an increase in the number of immune cells in AT that secrete cytokines involved in chronic low-grade inflammation that is characteristic of obesity-associated pathophysiology, namely, type II diabetes. A hallmark cytokine is IFN, which provides innate resistance against a broad range of viral infections. While the mechanism of action has yet to be fully elucidated, HFD-driven type I IFN signaling presents a potential target in treating a broad spectrum of obesity-associated co-morbidities.

Study Rationale: The objectives of this study were to elucidate the capacity of type 1 IFN to regulate inflammatory features in adipocytes, and to determine whether type 1 IFN signaling plays a role in the dysfunction of fibroblasts that drives obesity-associated metabolic syndrome. Thus, primary stromovascular fraction cells (SVFs) and 3T3L1 fibroblast cell line were treated with IFN-α and IFN-γ to recapitulate the phenotype of PDGRF-α+ BST2+ cell cluster. Next, 3T3L1 fibroblasts were cultured with conditioned medium from IFN-treated SVFs to determine whether SVFs secrete soluble factors that mitigate the ability of neighboring cells to differentiate into adipocytes.

Results and Discussion: From qPCR analysis of type I IFN signature genes, IFN-α treatment increased the expression of type I IFN-specific genes Mx1, Isg15, and Ifit3 by several-hundred-fold compared to negative controls in 3T3L1s, with similar patterns observed in the SVFs. These fold changes were significantly greater than expression levels from IFN-g treatment, suggesting that IFN-α cytokines selectively bind IFNAR receptors on fibroblasts to induce type I IFN responses. These experimental results run parallel with the finding that ectopic type I IFN signaling promotes insulin resistance in adipocytes, in turn contributing to the dysregulation of glucose homeostasis and inflammation-associated metabolic syndrome. Future studies should consider analyzing the effects of blocking type I IFN signaling in AT, which can play a crucial role in ameliorating diet- and obesity-associated insulin resistance.