Sex and Age but Not Body Mass Index (BMI) Predict Serum Retinol Binding Protein 4 (RBP4) and Transthyretin (TTR)...

Increased serum concentrations of retinol (vitamin A) and its binding protein retinol binding protein 4 (RBP4) have been linked to progressive obesity, type 2 diabetes, and reduced liver or kidney function. It has been suggested that body mass index (BMI) and serum RBP4 concentrations correlate. Whether this correlation is due to obesity or associated disorders such as insulin resistance or steatotic liver disease is not known. In circulation, RBP4 forms a complex with transthyretin (TTR). Whether the formation of the RBP4-TTR complex is altered with progressive obesity remains to be determined. The goal of this study was to establish whether serum RBP4, retinol, and TTR concentrations change with BMI in a population without diabetes or organ impairment. Fasting serum concentrations of RBP4, TTR, and retinol were measured by LC-MS/MS in individuals with a broad range of BMI (21-56 kg/m²), and RBP4-TTR-retinol complex formation was modeled. Sex and age explained a significant portion of the inter-individual variability in RBP4 (p < 0.01) and TTR (p = 0.02) concentrations, while BMI did not. Kinetic modeling suggested that the impact of sex on total RBP4 concentrations is driven by the sex difference in TTR concentrations. A negative correlation was observed between retinol concentrations and BMI but not between RBP4 concentrations and BMI. Collectively, our study shows that sex differences and possibly obesity-associated comorbidities rather than BMI explain prior findings of correlations of RBP4 and retinol concentrations with BMI. Our results emphasize the importance of measuring TTR, retinol, and RBP4 to assess disease associations.