LAUSR

Introduction: Excess or dysfunctional adipose tissue contributes to cardio-kidney-metabolic (CKM) syndrome through the secretion of proinflammatory mediators. However, fat depot-specific inflammatory profiles remain poorly characterized. Aims: Identify inflammatory plasma proteins associated with fat depots and with components of Stage 2 CKM syndrome. Methods: Among participants in the community-based Dallas Heart Study (DHS) 3 rd visit (2020-24), we measured 248 inflammatory plasma proteins using an ultra-high sensitivity immunoassay (NULISA™). Participants underwent measurements of subcutaneous and visceral fat volumes, and liver and thigh intramuscular fat percentages through whole-body MRI. Associations of individual proteins with fat depots at FDR significance were assessed using multivariable linear regression models adjusted for age, sex, and BMI. We further assessed the associations of identified proteins with individual components of Stage 2 CKM (metabolic syndrome, diabetes, CKD, hypertension, hypertriglyceridemia) using multivariable logistic models and with peak VO2 assessed through cardiopulmonary exercise test using multivariable linear models. Results: Among 104 participants (age 59±13 years; 50% female; 52% self-reported Black race), mean BMI was 30±9 kg/m 2 , subcutaneous fat volume 9±5 L, visceral fat volume 4±2 L; liver fat 4±5%; thigh intramuscular fat 9±3%. Nine proteins associated with higher visceral fat, 18 with higher subcutaneous fat, 11 with higher liver fat, and 12 with higher intramuscular fat (Figure). Of those, 6 uniquely associated with subcutaneous fat (FLT4, ICAM1, KDR, LILRB2, TEK, TLR3), 2 with liver fat (BST2, TREM2), 4 with intramuscular fat (CHI3L1, IL16, THBS2, TNFRSF1A), and none with visceral fat, while 14 proteins (CCL25, CRP, CSF1R, FGF21, FURIN, HGF, ICOSLG, IL18R1, IL1RN, IL6, LGALS9, LIF, SELE, TSLP) had shared associations with two or more fat depots. Among fat depot-associated proteins, 4 (15%) were associated with higher prevalence of diabetes; 9 (35%) with higher prevalence of CKD; 5 (19%) with higher prevalence of metabolic syndrome; and 12 (46%) with lower peak VO2. None were associated with hypertension or hypertriglyceridemia. Conclusion: We identified inflammatory plasma proteins associated with specific fat depots and with higher prevalence of stage 2 CKM syndrome components and lower cardiorespiratory fitness. They have potential as CKM biomarkers and might inform adiposity-related pathophysiology.