Inflammatory Proteomic Network Architecture of Visceral Adiposity and Cardiometabolic Traits

Background : Visceral adipose tissue (VAT) is strongly associated with cardiometabolic disease, but the network architecture connecting visceral adiposity to systemic inflammatory proteins and cardiometabolic traits remains poorly characterized. Methods : We applied an artificial intelligence (AI)-driven network integration approach to plasma inflammatory proteomics (Olink Explore 384) and cardiometabolic traits (VAT, HOMA-IR, glucose, systolic blood pressure [SBP], triglycerides [TG], LDL-C, and HDL-C) in the Vitamin D and Omega-3 Trial (VITAL) discovery cohort (n = 635). Network findings were evaluated for replication in the independent Cocoa Supplement and Multivitamin Outcomes Study (COSMOS) cohort (n = 371). Within-person associations between 2-year changes in proteins and corresponding clinical traits were also evaluated in VITAL. Results : VAT emerged as the central network hub, exhibiting direct connections with multiple cardiometabolic traits and more direct protein connections than any other trait. No inflammatory proteins were directly connected to glucose, HOMA-IR, or SBP in the integrated network; instead, their network connectivity with the inflammatory proteome was dependent on VAT. A triangular network motif linking VAT, HGF, and IL1RN was identified and independently replicated in COSMOS. Longitudinal analyses further showed that 2-year changes in VAT tracked with changes in HGF and IL1RN, while changes in HGF tracked with changes in IL1RN. Overall, 7 of 10 direct protein-trait connections identified at baseline remained significant longitudinally. PON3 exhibited connectivity with both VAT and HDL-C, with opposite-direction associations that remained significant longitudinally (VAT: 𝛽=-0.97, 𝑝=8×10-4; HDL-C: 𝛽=1.44,𝑝= 4×10-7). Conclusion : Visceral adiposity occupies a central position within the integrated inflammatory proteomic and cardiometabolic network. The reproducibility of the VAT-HGF-IL1RN network motif across cohorts and over time, together with the longitudinal stability of most protein-trait connections, supports a VAT-centered organization of inflammatory and cardiometabolic relationships. These findings provide a network-based framework for investigating molecular connections between visceral adiposity, lipid metabolism, and systemic inflammation.