Retinol-binding protein 4 (RBP4) is a 21 kDa lipocalin family protein primarily known for transporting vitamin A (retinol) from hepatic stores to peripheral tissues. Beyond its classical role in retinol transport, RBP4 has emerged as a significant regulator of lipid metabolism and energy homeostasis, with implications in obesity, insulin resistance, and metabolic diseases. 

RBP4 and Its Biological Function

RBP4 circulates in the bloodstream bound to retinol and interacts with transthyretin (TTR) to prevent renal clearance. Apart from its transport function, RBP4 acts as an adipokine secreted by adipocytes and hepatocytes, influencing systemic metabolic processes. Elevated RBP4 levels are correlated with obesity, type 2 diabetes mellitus (T2DM), insulin resistance, and cardiovascular risk factors, suggesting a role in metabolic dysregulation.

RBP4 in Lipid Metabolism and Thermogenesis

Recent research has elucidated a pivotal role for RBP4 in regulating lipid metabolism, particularly in brown adipose tissue (BAT), which is specialized for energy expenditure through adaptive thermogenesis. A 2025 study demonstrated that overexpression of RBP4 specifically in brown fat enhances canonical adrenergic signaling pathways, promoting lipolysis—the breakdown of lipids into free fatty acids (FFAs) and glycerol—and increasing energy expenditure (Park et al., 2025).

• Enhanced Lipolysis: Transgenic mice with brown fat-specific RBP4 overexpression showed elevated plasma glycerol and FFA levels, indicating increased systemic lipolysis. Ex vivo assays confirmed higher basal lipolysis rates in brown fat explants from these mice compared to controls.
• Adrenergic Signaling Activation: RBP4 positively regulates the β3-adrenergic receptor-cAMP-PKA pathway, which is essential for lipolysis and thermogenic activation in BAT. Knockdown of RBP4 in brown adipocytes attenuated this signaling, reducing lipolysis and fatty acid oxidation.
• Transcriptional Regulation: Transcriptome analyses revealed that RBP4 overexpression upregulates genes involved in lipid metabolism and thermogenesis, including those regulating fatty acid biosynthesis, uptake, and oxidative phosphorylation. This suggests RBP4 modulates a network of genes enhancing BAT function and systemic energy metabolism.
• Systemic Effects: Beyond BAT, RBP4 influences white adipose tissue (WAT) browning and systemic retinoid homeostasis, contributing to improved glucose control and body weight regulation in animal models. These findings position RBP4 as a potential therapeutic target for obesity and metabolic syndrome.

RBP4 and Lipolysis in Human Adipocytes

In humans, elevated RBP4 levels are associated with increased basal lipolysis and insulin resistance, particularly in obese individuals. Studies have shown:

• Direct Stimulation of Lipolysis: RBP4 treatment of human adipocytes in vitro increases basal lipolysis, releasing FFAs and glycerol.
• Macrophage Activation and Inflammation: RBP4 activates macrophages to produce pro-inflammatory cytokines such as TNFα, which further impair insulin-mediated suppression of lipolysis in adipocytes. This inflammatory milieu exacerbates systemic insulin resistance.
• Correlation with Metabolic Markers: Higher RBP4 expression in adipose tissue correlates with inflammatory markers and inversely with insulin sensitivity and glucose disposal, linking RBP4 to metabolic dysfunction in obesity.

RBP4 is a multifunctional protein that plays a significant role in lipid metabolism through its effects on adipose tissue lipolysis, thermogenesis, and systemic energy balance. Assay kits for RBP4 quantification are essential tools enabling detailed investigation of its physiological and pathological roles. Experimental models demonstrate that RBP4 enhances adrenergic signaling and lipid mobilization in brown fat, promoting thermogenesis and metabolic health. Conversely, elevated RBP4 in obesity contributes to increased lipolysis and inflammation, leading to insulin resistance.

Targeting RBP4, particularly in a tissue-specific manner such as in brown adipose tissue, offers a promising avenue for therapeutic intervention in metabolic diseases including obesity and T2DM. Continued research leveraging sensitive assay technologies will further clarify RBP4’s complex role in lipid metabolism and metabolic regulation.

References

Park, J.Y., Ha, E.S., Lee, J., Brun, P.J., Kim, Y., Chung, S.S., Hwang, D., Lee, S.A. and Park, K.S., 2025. The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway. Experimental & Molecular Medicine, pp.1-13.https://doi.org/10.1038/s12276-025-01411-6