Yadav Aprajita S, Czuba Lindsay C, Zhu Jerry, LaFrance Jeffrey, Authement Aurora K, Williams Lindsey, Chen Judy Y, Williams Estell, Parr Zoe, Khandelwal Saurabh, Kim Daniel, Rubinow Katya B, Isoherranen Nina
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA.
FASEB J. 2025 Jul 31;39(14):e70842. doi: 10.1096/fj.202501772R.
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/m), 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.
血清视黄醇（维生素A）及其结合蛋白视黄醇结合蛋白4（RBP4）浓度升高与进行性肥胖、2型糖尿病以及肝肾功能减退有关。有人提出体重指数（BMI）与血清RBP4浓度相关。这种相关性是由于肥胖还是相关疾病如胰岛素抵抗或脂肪性肝病所致尚不清楚。在循环中，RBP4与甲状腺素转运蛋白（TTR）形成复合物。随着进行性肥胖，RBP4-TTR复合物的形成是否改变仍有待确定。本研究的目的是确定在无糖尿病或器官损害的人群中，血清RBP4、视黄醇和TTR浓度是否随BMI变化。通过液相色谱-串联质谱法（LC-MS/MS）测量了BMI范围广泛（21-56 kg/m）个体的空腹血清RBP4、TTR和视黄醇浓度，并对RBP4-TTR-视黄醇复合物的形成进行了建模。性别和年龄解释了RBP4（p < 0.01）和TTR（p = 0.02）浓度个体间差异的很大一部分，而BMI则没有。动力学模型表明，性别对总RBP4浓度的影响是由TTR浓度的性别差异驱动的。观察到视黄醇浓度与BMI呈负相关，但RBP4浓度与BMI之间无相关性。总体而言，我们的研究表明，性别差异以及可能与肥胖相关的合并症而非BMI解释了先前RBP4和视黄醇浓度与BMI相关性的研究结果。我们的结果强调了测量TTR、视黄醇和RBP4以评估疾病关联的重要性。
