Retinol-Binding Protein 4 in Obesity-Associated Metabolic Dysfunction: Mechanisms, Controversies, and Therapeutic Opportunities

Retinol-binding protein 4 (RBP4) is the primary carrier of retinol in the circulation and is produced mainly by the liver. Interest in RBP4 expanded after reports of elevated circulating levels in insulin-resistant mice and some human populations, leading to its proposal as an adipokine, an immunometabolic mediator, and a biomarker of obesity-related metabolic disease. However, subsequent research has revealed that its biology is considerably more complex. The metabolic effects of RBP4 are influenced by multiple factors, including its tissue of origin, retinol-binding status, association with transthyretin, receptor interactions, renal clearance, and the surrounding inflammatory environment. This review summarizes current evidence linking RBP4 to insulin resistance, adipose tissue dysfunction, and type 2 diabetes, while distinguishing classical retinol-bound holo-RBP4–dependent signaling through STRA6 (stimulated by retinoic acid 6) from retinol- and STRA6-independent mechanisms involved in innate and adaptive immune activation. We also discuss the transcriptional regulation of RBP4, focusing on PPARγ (peroxisome proliferator-activated receptor γ), HMGA1 (high mobility group A1 protein), and HIF-1α (hypoxia-inducible factor 1α)-related hypoxia-responsive pathways. Available evidence suggests that these factors do not operate within a simple HIF-1α-PPARγ-RBP4 signaling axis but rather participate in interconnected regulatory networks that shape adipocyte differentiation, secretory function, and metabolic adaptation. Although higher circulating RBP4 concentrations have been associated with adverse metabolic traits and an increased risk of type 2 diabetes, their clinical interpretation remains challenging because of the influence of renal function, vitamin A status, molecular heterogeneity, and methodological differences between assays. Pharmacological approaches to lower RBP4 are now feasible, but whether systemic reduction is beneficial remains uncertain. Targeting the specific pathogenic actions of RBP4, while preserving its essential role in retinol transport, may offer a more effective therapeutic strategy for metabolic disease.