Healthy adipocytes provide a protective environment by limiting viral infection through cell-cell communication

Adipocytes, long regarded primarily as energy storage cells, are increasingly recognized as active players in immune regulation. In metabolic disorders such as obesity and diabetes--conditions characterized by adipocyte dysfunction--patients often exhibit worsened outcomes following viral infections. However, the role of healthy adipocytes in modulating antiviral immunity remains poorly understood. Here, we demonstrate that healthy adipocytes secrete factors that confer antiviral protection to neighboring cells. We developed a fully human pluripotent stem cell (hPSC)-derived system including adipocytes, immune, and vascular cells to evaluate the antiviral capacity and infectivity of various cell types. Our cell system has the advantage of being of human origin, as opposed to animal models. Through our technological development, we have removed cell culture medium as a variable by adapting all cell types to a single base medium. We found that only adipocytes could induce an antiviral state in adjacent mural and immune cells. This unique immunomodulatory capacity is mediated, at least in part, by the STING-dependent secretion of low levels of interferon-alpha (IFN-) from healthy adipocytes. Notably, pharmacological induction of metabolic dysfunction in adipocytes diminished their antiviral activity, revealing a previously unrecognized link between metabolic health and antiviral defense. These findings identify a novel role for adipocytes in orchestrating local antiviral responses and provide new insight into how metabolic dysfunction may compromise host defense during viral infections.