Retinol-Binding Protein-4 Predicts Visceral Adiposity and Related Inflammatory–Cardiometabolic Profiles in Women

Visceral adiposity is a key contributor to cardiometabolic risk through links to insulin resistance, inflammation, and atherogenic dyslipidemia. In women, this is especially relevant during menopausal transition, when hormonal shifts increase visceral fat and cardiometabolic vulnerability. Yet factors predisposing to visceral adiposity remain unclear, emphasizing the need to identify its determinants as targets to modulate visceral fat and associated metabolic risk.We studied 410 healthy women (290 premenopausal, 120 postmenopausal) under controlled hormonal conditions. Serum measures included fat-storage–related hormones/proteins, cardiovascular risk (atherogenic lipids, inflammatory and oxidation) parameters. Regional fat predictors were identified by regression analyses. Mediation models examined whether the predictor’s association with visceral fat corresponded to downstream cardiometabolic outcomes.Higher visceral fat (+ 50.7%), elevated retinol-binding-protein-4 (RBP4) (+ 23.6%), and lower growth hormone (GH) (− 63.8%) levels were found in postmenopausal compared to premenopausal women (p < 0.001). RBP4 was the main positive predictor of visceral adiposity (6.5% variance%, p < 0.001), surpassing insulin, while GH was the strongest negative predictor (− 13%). Mediation models showed that RBP4 associated with metabolic risk profiles through both visceral fat–related and fat-independent pathways. The strongest associations were observed for the inflammatory profile. RBP4 demonstrated visceral-fat–related associations with (hsCRP β = 0.0617; IL-6 β = 0.036, p < 0.001). Conversely, a fat-independent pathway showed inverse associations with these markers (hsCRP β= −0.0678; IL-6 β= −0.0650, p < 0.05), suggesting a weaker anti-inflammatory profile, and predominance of the visceral fat-associated pro-inflammatory pathway.Furthermore, RBP4 demonstrated visceral-fat–mediated associations with LDL-C, triglycerides, and ApoB (β = 0.0136, 0.0063, 0.0037; p < 0.001), alongside fat-independent associations (β 0.0279, 0.0129, 0.0082; p < 0.001) suggesting involvement of both visceral-fat–related and direct pathways. The association with insulin resistance was primarily through visceral fat (HOMA-IR β = 0.0172; p < 0.001), while the association with the oxidative parameter, homocysteine, was exclusively independent (β = 0.033; p = 0.029).Overall, RBP4 emerges as a key predictor of visceral adiposity, with both visceral-fat–related and fat-independent associations linked to cardiometabolic risk. These findings highlight RBP4 as a potential contributor to visceral fat–related vulnerability in women, warranting further investigations in longitudinal and male cohorts.