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Obesity triggers chronic low-grade inflammation contributing to cardiovascular and metabolic diseases. Over-release of adipokines and pro-inflammatory mediators by white adipose tissue (WAT) enhances inflammation through a feedforward loop involving endothelial and immune cells, promoting atherosclerosis. Our previous studies showed that in vivo gene transfer of the longevity-associated variant (LAV) of BPIFB4 restores endothelial and cardiac function and reduces systemic inflammation in mouse models. Here we investigated the anti-inflammatory potential of orally administered recombinant rhLAV-BPIFB4 in ApoE-/- mice fed a high-fat diet to elucidate its role in modulating endothelial dysfunction primed by adipose tissue inflammation. We studied n = 5 ApoE-/- mice on standard diet (SD), n = 5 (VEH-HFD) and n = 6 (LAV-HFD) ApoE-/- mice fed high-fat diet without or with rhLAV-BPIFB4 protein. Primary pre-adipocyte cultures were established from epididymal WAT to evaluate CD45+CD38+ leukocyte infiltration, inflammatory profile of pre-adipocytes, and ex vivo effects of conditioned media on vessels. Oral administration of rhLAV-BPIFB4 in ApoE-/- mice fed high-fat diet dampens atherosclerosis by preserving endothelial integrity and reducing ICAM+ and CD68+ cell infiltration. Despite unchanged adiposity, systemically rhLAV-BPIFB4 reduces pro-inflammatory cytokines (IL-1α/β, TNF-α, IL-6) while mildly increasing IL-10 levels. Supernatants from pre-adipocytes treated with rhLAV-BPIFB4 demonstrate similar anti-inflammatory cytokine profiles. Conditioned media from rhLAV-treated eWAT ex vivo restores endothelial function in dysfunctional arteries (VEH-HFD vs LAV-HFD, ***p < 0.001). Collectively our data show that targeting adipocyte-associated inflammation, LAV-BPIFB4 emerges as a promising therapeutic strategy to counteract endothelial dysfunction in obesity.