Interplay of retinol binding protein 4 with obesity and associated chronic alterations (Review)

Abstract

Obesity is a multifactorial disease, defined as excessive fat deposition in adipose tissue. Adipose tissue is responsible for the production and secretion of numerous adipokines that induce metabolic disorders. Retinol‑binding protein 4 (RBP4) is an adipokine that transports vitamin A or retinol in the blood. High levels of RBP4 are associated with development of metabolic disease, including obesity, insulin resistance (IR), metabolic syndrome, and type 2 diabetes (T2D). The present review summarizes the role of RBP4 in obesity and associated chronic alterations. Excessive synthesis of RBP4 contributes to inflammatory characteristic of obesity by activation of immune cells and release of proinflammatory cytokines, such as TNFα and ILs, via the Toll‑like receptor/JNK pathway. The retinol‑RBP4 complex inhibits insulin signaling directly in adipocytes by activating Janus kinase 2 (JAK2)/STAT5/suppressor of cytokine signaling 3 signaling. This mechanism is retinol‑dependent and requires vitamin A receptor stimulation by retinoic acid 6 (STRA6). In muscle, RBP4 is associated with increased serine 307 phosphorylation of insulin receptor substrate‑1, which decreases its affinity to PI3K and promotes IR. In the liver, RBP4 increases hepatic expression of phosphoenolpyruvate carboxykinase, which increases production of glucose. Elevated serum RBP4 levels are associated with β‑cell dysfunction in T2D via the STRA6/JAK2/STAT1/insulin gene enhancer protein 1 pathway. By contrast, RBP4 induces endothelial inflammation via the NF‑κB/nicotinamide adenine dinucleotide phosphate oxidase pathway independently of retinol and STRA6, which stimulates expression of proinflammatory molecules, such as vascular cell adhesion molecule 1, E‑selectin, intercellular adhesion molecule 1, monocyte chemoattractant protein 1 and TNFα. RBP4 promotes oxidative stress by decreasing endothelial mitochondrial function; overall, it may serve as a useful biomarker in the diagnosis of obesity and prognosis of associated disease, as well as a potential therapeutic target for treatment of these diseases.

Keywords: insulin resistance; obesity; oxidative stress; retinol‑binding protein 4; type 2 diabetes.

Figure 1.

Molecular mechanisms of RBP4 in obesity and associated disease. (A) In adipocytes, the retinol-RBP4 complex directly inhibits insulin signaling by activating the JAK2/STAT5/SOCS3 pathway, leading to IR. (B) In adipose tissue, macrophages, retinol-RBP4 and RBP4 interact with TLR2 and TLR4/MD2 and downstream pathways of MyD88 and TRIF, releasing TNFα, IL-6, MCP-1, INF-γ, IL-1β, IL-2, IL-12, IL-8 and IL-10. This results in activation of the immune system and promotes an inflammatory state as well as inhibition of insulin signaling. (C) RBP4 induces NF-κB and NADPH oxidase-dependent endothelial inflammation, leading to development of OS by mitochondrial dysfunction. (D) RBP4 increases hepatic expression of PEPCK, thus increasing glucose production in the liver. (E) In skeletal muscle, RBP4 is associated with high serine 307 phosphorylation of IRS-1, which decreases its affinity for PI3K and inhibits insulin signaling. (F) Retinol-RBP4 promotes β-cell dysfunction via the JAK2/STAT1/ISL-1 pathway. (G) Aforementioned mechanisms promote development of hyperglycemia. PKB, Protein kinase B (PKB); AP-1, Activator protein 1; Drp1, Dynamin-related protein 1; Fis1, Mitochondrial fission 1 protein; GLUT 4, Glucose transporter type 4; ICAM-1, Intercellular Adhesion Molecule 1; IRS1, Insulin receptor substrate-1; ISL-1, Insulin gene enhancer protein; JAK2, Janus Kinase 2; MCP-1, Monocyte chemotactic protein-1; MCP-1, Monocyte chemotactic protein-1; Mfn1, Mitofusin-1; MyD88, Myeloid differentiation primary response 88; NOX2, NADPH oxidase; PEPCK, Phosphoenolpyruvate carboxykinase; RBP4, Retinol Binding Protein 4; ROS, reactive oxygen species; SOCS3, Suppressor of cytokine signaling 3; TLR, Toll-like receptor; TNFα-R, tumor necrosis factor α receptor; TRIF, TIR-domain-containing adapter-inducing interferon-β; VCAM-1, Vascular cell adhesion protein 1.

Figure 2.

Schematic representation of alterations in RBP4 levels in obesity and its association with other types of pathology. Hyperglycemia and lipid dysregulation promote obesity, which induces the development of other pathology. Increased levels of RBP4 is a common factor.