Objectives: In context of metabolic disease, adipocytes were shown to pathologically interact with the immune system. When becoming obese, these cells drive inflammation in adipose tissue, which alters local and systemic regulation of metabolism. However, how adipocytes interact with immune cells in context of viral infection is largely unknown. Our objective was to investigate the impact of virus-induced activation of the immune system on adipose tissue metabolism and the underlying benefit of these changes to the organism. Materials and methods: Mice were infected with murine cytomegalovirus (mCMV) as a model of human infection. To determine the impact of mCMV infection on adipose tissue physiology, density of visceral adipose tissue (VAT) was measured by x-ray and adipocyte size by histology. To investigate the impact of immune-adipocyte interactions in vitro, we made use of the 3T3-L1 model. Lipid content was quantified histologically with Oil red O staining or by flow cytometry after BODIPY staining, upon treatment with different cytokines. The impact of IFNγ on key metabolic genes was determined by micro-array and confirmed by RT-PCR analysis. The role of specific immune cells, cytokines and stress receptors was determined through antibody-mediated neutralization or by using genetic mouse models. Mass spectrometry was used to determine the lipidomic profile of mouse plasma after infection. Finally, to determine the impact of lipids on the immune system, we made use of the A20 B cell line. Cells were characterized with flow cytometry and Seahorse analysis upon treatment with fatty acids. Results: Upon mCMV infection, VAT transiently decreases in size and density, with a maximum effect after 3 days. Adipocytes increase expression of ligands for the activating NK cell receptor NCR1. NK cells are activated through NCR1 and produce high amounts of IFNγ. This cytokine directly targets adipocytes and downregulates the key transcription factor PPARγ and its target genes. The result is adipocyte size reduction, and release of fatty acids such as oleic acid into the bloodstream. This effect was prevented if mice were deficient for NCR1, IFNγ, or the IFNγ receptor on adipocytes and if NK cells were depleted using antibodies. Serum levels of oleic acid were increased in particular, and this fatty acid promotes ATP production and increases activation of A20 B cells in vitro. Importantly, in animals deficient for IFNγ, B cell activation was significantly reduced. Conclusion: Infection causes activation of NK cells in VAT, which induces lipid release by adipocytes following direct stimulation by IFNγ. The increase in systemic lipids promotes the activation of B cells. Our findings provide a physiological explanation for the interactions between the immune system and adipose tissue in the context of inflammation. A better understanding of these mechanisms of metabolic regulation by the immune system can be highly beneficial for comprehension and treatment of infection-induced complications in the context of the metabolic disease.