Chronic viral infection aggravates white adipose tissue dysfunction and liver pathology in obesity

White adipose tissue (WAT) plays a central role in maintaining systemic metabolic homeostasis by buffering lipid flux throughout the body. Impairment of this lipid-buffering capacity is a hallmark of obesity and has also been observed during chronic viral infection. Such dysfunction is closely associated with ectopic fat accumulation, particularly in the liver. We hypothesized that the coexistence of obesity and chronic viral infection exacerbates WAT dysfunction, thereby promoting liver pathology. However, the specific response of obese WAT to chronic viral infection – and its downstream impact on liver health – remains to be explored. To investigate this interaction, we employed a model of chronic viral infection in mice using lymphocytic choriomeningitis virus (LCMV) clone 13. In obese hosts, chronic infection caused sustained WAT depletion and progressive weight loss, accompanied by a reduction of Tim-4 + eWAT-resident macrophages and features reminiscent of lipodystrophy and aggravated metabolic dysfunction-associated steatotic liver disease (MASLD). Depletion of CD8 + T cells, the key mediators of LCMV-driven weight loss in lean mice, only modestly attenuated weight loss and did not ameliorate liver pathology in obese mice. Likewise, therapeutic interventions including TNF-α blockade and glycemic control with metformin did not reverse infection-induced weight loss; moreover, TNF-α blockade failed to improve liver pathology. Collectively, these findings reveal a previously unrecognized crosstalk between WAT and the liver in infection-driven MASLD, highlight distinct responses in WAT of obese mice compared to their lean counterpart, and underscore the increased susceptibility to virus-induced metabolic complications in obesity.