UNLABELLED: The biomarkers connecting obesity and cardiometabolic diseases are not fully understood. We aimed to 1) evaluate the associations between BMI, waist circumference (WC), and ∼5,000 plasma proteins (SomaScan V4), 2) identify protein signatures of BMI and WC, and 3) evaluate the associations between the protein signatures and cardiometabolic health, including metabolically unhealthy obesity and type 2 diabetes incidence in the Singapore Multi-Ethnic Cohort Phase 1 (MEC1). Among 410 BMI-associated and 385 WC-associated proteins, we identified protein signatures of BMI and WC and validated them in an independent data set across two time points and externally in the Atherosclerosis Risk in Communities (ARIC) study. The BMI and WC protein signatures were highly correlated with total and visceral body fat, respectively. Furthermore, the protein signatures were significantly associated with cardiometabolic risk factors and metabolically unhealthy obesity. In prospective analyses, the protein signatures were strongly associated with type 2 diabetes risk in MEC1 (odds ratio per SD increment in WC protein signature 2.84
95% CI 2.47-3.25) and ARIC (hazard ratio 1.98
95% CI 1.88-2.08). Our protein signatures have potential uses in the monitoring of metabolically unhealthy obesity. ARTICLE HIGHLIGHTS: We evaluated the associations between ∼5,000 plasma proteins and BMI and waist circumference (WC) in a multiethnic Asian population. We identified 410 proteins associated with BMI and 385 proteins associated with WC and derived protein signatures of BMI and WC, which we validated externally in a U.S. cohort. Both the BMI and WC protein signatures were strongly associated with cardiometabolic risk factors, metabolically unhealthy obesity, and risk of obesity, metabolic syndrome, and type 2 diabetes. Our protein signatures have potential uses in monitoring metabolically unhealthy obesity.