Type I interferon sensing unlocks dormant adipocyte inflammatory potential

Calvin C. Chan, Michelle S. M. A. Damen, Maria E. Moreno-Fernandez, Traci E. Stankiewicz, Monica Cappelletti, Pablo C. Alarcon, Jarren R. Oates, Jessica R. Doll, Rajib Mukherjee, Xiaoting Chen, Rebekah Karns, Matthew T. Weirauch, Michael A. Helmrath, Thomas H. Inge and Senad Divanovic ()
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Calvin C. Chan: Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine
Michelle S. M. A. Damen: University of Cincinnati College of Medicine
Maria E. Moreno-Fernandez: University of Cincinnati College of Medicine
Traci E. Stankiewicz: University of Cincinnati College of Medicine
Monica Cappelletti: University of Cincinnati College of Medicine
Pablo C. Alarcon: Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine
Jarren R. Oates: Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine
Jessica R. Doll: University of Cincinnati College of Medicine
Rajib Mukherjee: University of Cincinnati College of Medicine
Xiaoting Chen: Cincinnati Children’s Hospital Medical Center
Rebekah Karns: University of Cincinnati College of Medicine
Matthew T. Weirauch: University of Cincinnati College of Medicine
Michael A. Helmrath: Cincinnati Children’s Hospital Medical Center
Thomas H. Inge: Children’s Hospital Colorado
Senad Divanovic: Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract White adipose tissue inflammation, in part via myeloid cell contribution, is central to obesity pathogenesis. Mechanisms regulating adipocyte inflammatory potential and consequent impact of such inflammation in disease pathogenesis remain poorly defined. We show that activation of the type I interferon (IFN)/IFNα receptor (IFNAR) axis amplifies adipocyte inflammatory vigor and uncovers dormant gene expression patterns resembling inflammatory myeloid cells. IFNβ-sensing promotes adipocyte glycolysis, while glycolysis inhibition impeded IFNβ-driven intra-adipocyte inflammation. Obesity-driven induction of the type I IFN axis and activation of adipocyte IFNAR signaling contributes to obesity-associated pathogenesis in mice. Notably, IFNβ effects are conserved in human adipocytes and detection of the type I IFN/IFNAR axis-associated signatures positively correlates with obesity-driven metabolic derangements in humans. Collectively, our findings reveal a capacity for the type I IFN/IFNAR axis to regulate unifying inflammatory features in both myeloid cells and adipocytes and hint at an underappreciated contribution of adipocyte inflammation in disease pathogenesis.

Date: 2020
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DOI: 10.1038/s41467-020-16571-4

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