Abstract Body: Central obesity is related to an elevated risk of type 2 diabetes (T2D) and cardiovascular diseases (CVD), partly through chronic inflammation caused by metabolically active visceral adipose tissue (VAT). However, how changes in VAT modulated secretion of circulating inflammatory proteins and its interplay with glycemic control remain unclear. Our study aims to investigate the associations of concurrent longitudinal changes in VAT, glycemic control, and inflammatory proteomic profiles in a well-phenotyped cohort of middle- to older-aged US adults, to help elucidate mechanisms underlying obesity and risk of T2D and CVD.
We analyzed 562 participants (age 63.7±6.1) in the prospective VITamin D and OmegA-3 TriaL (VITAL) study with baseline and 2-year data for DXA-derived VAT mass, plasma proteomics (Olink Explore 384 inflammation panel), and glycemic traits: fasting glucose, hemoglobin A1c (HbA1c), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). We computed within-person 2-year changes (Δ) in VAT and glycemic traits and assessed their associations with individual Δproteins using multivariable linear models adjusting for baseline exposure and protein levels, demographics, lifestyle factors, and VITAL treatment group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed.
Over 2 years, participants had a non-significant increase in VAT mass (mean=9.1g, p=0.66), glucose (mean=1.26mg/dL, p=0.09), HbA1c (mean=0.03%, p=0.24), and HOMA-IR (mean=1.26, p=0.11). VAT gain was significantly associated with concurrent changes in 34 inflammatory proteins (false discovery rate [FDR]<0.05), including increases in FSTL3, HGF, IL18R1, and decreases in IL17RB, and CD276. Among them, 19 proteins were also related to Δglucose, 11 with ΔHbA1c, and 25 with ΔHOMA-IR; CD22, ENPP7, IL18R1, LGALS9, LILRB4, SERPINB8, SIGLEC1, TLR3, TREM2 were shared across all glycemic traits. Proteins related to ΔVAT were enriched onto the cytokine-cytokine receptor interaction pathway.
Longitudinal VAT change and concurrent changes in glycemic control were accompanied by distinct proteomic changes reflective of inflammation, particularly through cytokine signaling. These findings underscore a potential biological link between VAT change, metabolic dysregulation, and inflammation, highlighting VAT as a promising upstream intervention to target in T2D and CVD prevention.