Severe obesity is associated with coordinated ACE2 upregulation and OAS1 downregulation across blood and adipose precursor cells

Obesity is associated with immune dysfunction and increased susceptibility to viral infections, yet the molecular alterations potentially contributing to this increased vulnerability remain poorly defined. Here, we integrated transcriptional, epigenetic, and circulating measurements to define immunometabolic signatures associated with obesity. We analyzed individuals with severe obesity (PwSO) and without obesity (Controls), assessing the expression of SARS-CoV-2-related host factors and interferon-stimulated genes in peripheral blood mononuclear cells (PBMCs), adipocyte precursor cells (APCs), and serum. Epigenome-wide DNA methylation profiling was performed and integrated with an independent SARS-CoV-2 dataset. PwSO exhibited increased ACE2 mRNA and protein expression in PBMCs and APCs, along with elevated circulating ACE2 levels, which correlated with body mass index (BMI). Integrated methylome analyses revealed enrichment of immune and antiviral pathways shared with SARS-CoV-2 infection, including hypomethylation at cg06168856, a CpG site linked to OAS1 . Notably, OAS1 expression was significantly reduced in both PBMCs and APCs and was positively associated with the hypomethylation at the cg06168856. Overall, these findings are consistent with a coordinated molecular imbalance characterized by ACE2 upregulation and OAS1 downregulation, supported by epigenomic convergence on immune and antiviral pathways. This pattern may be relevant to host-virus interactions and highlights ACE2 together with OAS1 as complementary molecular markers of obesity-associated immunometabolic alterations.