Obese individuals exhibit considerable heterogeneity in developing cardiovascular diseases, yet the underlying molecular mechanisms remain unclear. We aimed to investigate the prospective associations between obesity phenotypes, serum proteomics, and carotid atherosclerosis (CAS) incidence.

This cohort study included 3162 participants from the Guangzhou Nutrition and Health Study, with 413 proteins profiled from 6803 serum samples collected at three time-points. Obesity phenotypes included metabolically healthy non-obesity (MHNO) and metabolically healthy/unhealthy obesity (MHO/MUO).

We identified 11 proteins influenced by MUO (vs. MHO) over time, with their combined score positively associated with incident CAS (HR: 1.16; 95% CI: 1.01–1.34). Additionally, 8 proteins were prospectively associated with MHO-to-MUO transition, which increased the performance of traditional risk factors in predicting this transition (P < 0.001). Among the 8 proteins, bidirectional mediation effects were observed between pigment epithelium-derived factor (PEDF) (36.8%; P = 0.025) and the MHO-to-MUO transition (20.5%; P = 0.010) on CAS incidence. The PEDF genetic risk score was positively associated with MHO-to-MUO transition (OR: 1.20; 95% CI: 1.00–1.43). Our main findings were validated in both the internal and external validation cohorts.

This population-scale proteomics study broadens our understanding of the mechanisms underlying obesity heterogeneity and CAS, providing potential targets for the prevention of CAS.

This study was supported by the National Natural Science Foundation of China, the Key Research and Development Program of Guangzhou, “Pioneer” and “Leading goose” R&D Program of Zhejiang, and the 5010 Program for Clinical Researches of the Sun Yat-sen University.

Obesity heterogeneity

Circulating proteins

Carotid atherosclerosis

Prospective study

© 2025 The Author(s). Published by Elsevier B.V.