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.

Longitudinal Change of Plasma Retinol-Binding Protein 4 and its Relation to Neurological-Function Recovery, Relapse, and Death in Acute Ischemic Stroke Patients

“…These findings indicated that RBP4 could be considered as a biomarker to predict the risk and severity of AIS. This might be because: (1) RBP4 promoted endothelial cell inflammation through the nuclear factor-kappaB (NF-κB)/nicotinamide adenine dinucleotide phosphate oxidase (NADPH) pathway (Flores-Cortez et al 2022); meanwhile, inflammation played an important role in the pathogenesis of AIS (Jin et al 2013). Thus,…”

“…stress by reducing endothelial mitochondrial function (Liu et al 2014, Flores-Cortez et al 2022; meanwhile, oxidative stress could induce brain injury, which was related to the pathogenesis of AIS (Hu et al 2022, Pawluk et al 2022, so RBP4 might accelerate the occurrence and severity of AIS. However, it is necessary to further clarify the specific mechanism of RBP4 to promote the development and progression of AIS.…”

Transcriptome-based selection and validation of optimal reference genes in perirenal adipose developing of goat (Capra hircus)

“…RBP4 is a useful biomarker for diagnosing obesity and the prognosis of related diseases ( 40 ), while IDH2 affects brown adipose tissue thermogenesis ( 41 ). In this study, RBP4 and IDH2 were differentially expressed based on the RNA-seq data (data not shown).…”

Mirror image serum lipid carrier protein profiles in pup and lactating mother Atlantic grey seals reflect contrasting resource mobilisation challenges

“…Intriguingly, RBP4 is now also recognised as an adipokine with several roles in metabolism including insulin regulation (Aigner and Datz, 2011;Nankam and Blueher, 2021;Flores-Cortez et al, 2022;Ji et al, 2022). It is secreted by the liver and adipocytes such that the increase in serum RBP4 in pups with time could be directly due to the increase in blubber adipocyte mass, and it may play other important roles in controlling the metabolism in pups as they accumulate extensive body stores in preparation for weaning.…”