Prospective Relation of Circulating Adipokines to Incident Metabolic Syndrome: The Framingham Heart Study

BACKGROUND: Adipokines are elaborated by adipose tissue and are associated with glycemic, lipid, and vascular traits. We hypothesized that in a cross‐sectional analysis circulating adipokines are altered among subsets of obesity stratified by presence versus absence of metabolic syndrome (MetS) and prospectively predict the incidence of MetS. METHODS AND RESULTS: Participants in the community‐based Framingham Third Generation Cohort who attended examination cycle 1 were included in the study (2002–2005; N=3777, mean age, 40 years; 59% women). Circulating adiponectin, leptin, leptin receptor, fetuin‐A, fatty acid–binding protein 4, and retinol binding protein 4 were assayed and related to incident MetS in follow‐up (mean 6 years). The adipokines were compared among individuals with excess body weight (body mass index ≥25 kg/m(2)) and prevalent MetS, excess body weight without MetS (metabolically healthy obese), and normal‐weight with MetS (metabolically obese, normal‐weight) with normal‐weight participants without MetS as a referent. Metabolically healthy obese individuals (n=1467) had higher circulating levels of fetuin‐A and fatty acid–binding protein 4 but lower levels of leptin, leptin receptor, and adiponectin (P<0.001 for all). The adipokine panel was associated with incident MetS (263 new‐onset cases; P=0.002). Higher circulating concentrations of retinol‐binding protein 4 and fetuin‐A were associated with incidence of MetS (odds ratio per 1‐SD increment log marker, 1.21; 95% CI, 1.03–1.41 [P=0.02] and 1.17; 95% CI, 1.01–1.34 [P=0.03], respectively). CONCLUSIONS: In our community‐based sample of young to middle‐aged adults, metabolically healthy obese individuals demonstrated an adverse adipokine profile. Higher circulating levels of retinol‐binding protein 4 and fetuin‐A marked future cardiometabolic risk.