AbstractPatients with COVID-19 frequently manifest adipose atrophy, weight loss and cachexia, which significantly contribute to poor quality of life and mortality^1,2. Browning of white adipose tissue and activation of brown adipose tissue are effective processes for energy expenditure^3–7; however, mechanistic and functional links between SARS-CoV-2 infection and adipose thermogenesis have not been studied. In this study, we provide experimental evidence that SARS-CoV-2 infection augments adipose browning and non-shivering thermogenesis (NST), which contributes to adipose atrophy and body weight loss. In mouse and hamster models, SARS-CoV-2 infection activates brown adipose tissue and instigates a browning or beige phenotype of white adipose tissues, including augmented NST. This browning phenotype was also observed in post-mortem adipose tissue of four patients who died of COVID-19. Mechanistically, high levels of vascular endothelial growth factor (VEGF) in the adipose tissue induces adipose browning through vasculature–adipocyte interaction. Inhibition of VEGF blocks COVID-19-induced adipose tissue browning and NST and partially prevents infection-induced body weight loss. Our data suggest that the browning of adipose tissues induced by COVID-19 can contribute to adipose tissue atrophy and weight loss observed during infection. Inhibition of VEGF signaling may represent an effective approach for preventing and treating COVID-19-associated weight loss.