The association between retinol-binding protein 4 and risk of type 2 diabetes: A systematic review and meta-analysis.

Retinol-binding protein 4 (RBP4) was controversially associated with type 2 diabetes mellitus (T2DM). This meta-analysis aimed at evaluating the association between RBP4 level and T2DM risk. MEDLINE and EMBASE were searched to identify relevant studies up to 3 December 2022. Random effects model was used to pool multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Publication bias was estimated by Funnel plot and Egger's test, it was considered to be significant when P < 0.05. Eight studies including 8087 participants were finally included. Compared to those with the lowest level, subjects with the highest level of RBP4 have a higher risk of T2DM (OR = 1.47, 95% CI: 1.16-1.78, P < 0.001, I2 = 86.9%). No publication bias among the included studies was found (t = 0.94, P = 0.377). This meta-analysis indicated that high RBP4 level was associated with increasing risk of T2DM.

Discovery of phenylpyrrolidine derivatives as a novel class of retinol binding protein 4 (RBP4) reducers.

Retinol-binding protein 4 (RBP4) is a potential drug target for metabolic and ophthalmologic diseases. A high-throughput screening of our compound library has identified a small-molecule RBP4 reducer 7a, as a hit compound. Aiming to provide a suitable tool for investigating the pharmacological effects of RBP4 reducers, we conducted a structure-activity relationship study of 7a. Exploration of the aryl head, oxazole core, and propanoic acid tail of 7a resulted in the discovery of novel, potent, and orally available phenylpyrrolidine derivatives 43b and 43c. Compound 43b had a potent and long-lasting blood RBP4-level-reducing effect when orally administered to mice at a dose as low as 0.3 mg/kg.

Predicting the protein composition of human urine in normal and pathological states: Quantitative description based on Dent1 disease (CLCN5 mutation).

KEY POINTS: The presence of plasma proteins in urine is difficult to interpret quantitatively. It may be a result of impaired glomerular filtration or impaired proximal tubule (PT) reabsorption, or both. Dent1 disease (CLCN5 mutation) abolishes PT protein reabsorption leaving glomerular function intact. Using urine protein measurements from patients with Dent1 disease and normal individuals, we devised a mathematical model that incorporates two PT transport processes with distinct kinetics. This model predicts albumin, α1 -microglobulin (α1 -m), ß2 -microglobulin (ß2 -m) and retinol-binding protein 4 (RBP4) urine concentrations. Our results indicate that the urinary excretion of ß2 -m and RBP4 differs from that of albumin and α1 -m in their sensitivity to changes in the glomerular filtration rate, glomerular protein leak, tubular protein uptake via endocytosis and PT water reabsorption. The model predicts quantitatively how hyperfiltration and glomerular leak interact to promote albuminuria. Our model should contribute to improved understanding and interpretation of urine protein measurements in renal disease. ABSTRACT: To clarify the relative contributions of glomerular filtration and tubular uptake to urinary protein excretion, we developed a mathematical model of protein reabsorption in the human proximal tubule (PT) using Michaelis-Menten kinetics and molar urinary protein measurements taken from human Dent1 disease (CLCN5 loss-of-function mutation). ß2 -Microglobulin (ß2 -m) and retinol-binding protein 4 (RBP4) are normally reabsorbed with 'very high' efficiency uptake kinetics and fractional urinary excretion of 0.025%, whereas albumin and α1 -microglobulin (α1 -m) are reabsorbed by 'high' efficiency uptake kinetics and 50-fold higher fractional urinary excretion of 1.15%. Our model correctly predicts the urinary ß2 -m, RBP4 and α1 -m content in aristolochic acid nephropathy, and elevated ß2 -m excretion with increased single nephron glomerular filtration rate (SNGFR) following unilateral-nephrectomy. We explored how altered endocytic uptake, water reabsorption, SNGFR and glomerular protein filtration affect excretion. Our results help to explain why ß2 -m and RBP4 are more sensitive markers of PT dysfunction than albumin or α1 -m, and suggest that reduced PT sodium and water reabsorption in Fanconi syndrome may contribute to proteinuria. Transition of albumin excretion from normal to microalbuminuria, a 5-fold increase, corresponds to a 3.5-fold elevation in albumin glomerular filtration, supporting the use of microalbuminuria screening to detect glomerular leak in diabetes. In macroalbuminuria, small albumin permeability changes produce large changes in excretion. However, changes in SNGFR can alter protein excretion, and hyperfiltration with glomerular leak can combine to increase albuminuria. Our model provides a validated quantitative description of the transport processes underlying the protein composition of human urine in normal and pathophysiological states.

Does Bariatric Surgery Improve Obesity Associated Comorbid Conditions.

Obesity is a constantly growing health problem which reduces quality of life and life expectancy. Bariatric surgery for obesity is taken into account when all other conservative treatment modalities have failed. Comparison of the multidisciplinary programs with bariatric surgery regarding to weight loss showed that substantial and durable weight reduction have been achieved only with bariatric surgical treatments. However, the benefits of weight loss following bariatric procedures are still debated regarding the pro-inflammatory and metabolic profile of obesity.

Plasma Retinoid Concentrations Are Altered in Pregnant Women.

Vitamin A is vital to maternal-fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women (n = 23) during two stages of pregnancy (25-28 weeks gestation and 28-32 weeks gestation) as compared to ≥3 months postpartum. It was hypothesized that plasma retinol, retinol binding protein 4 (RBP4), transthyretin and albumin concentrations would decline during pregnancy and return to baseline by 3 months postpartum. At 25-28 weeks gestation, plasma retinol (-27%), 4-oxo-13-cis-retinoic acid (-34%), and albumin (-22%) concentrations were significantly lower, and all-trans-retinoic acid (+48%) concentrations were significantly higher compared to ≥3 months postpartum in healthy women. In addition, at 28-32 weeks gestation, plasma retinol (-41%), retinol binding protein 4 (RBP4; -17%), transthyretin (TTR; -21%), albumin (-26%), 13-cis-retinoic acid (-23%) and 4-oxo-13-cis-retinoic acid (-48%) concentrations were significantly lower, whereas plasma all-trans-retinoic acid concentrations (+30%) were significantly higher than ≥3 months postpartum. Collectively, the data demonstrates that in healthy pregnancies, retinol plasma concentrations are lower, but all-trans-retinoic acid concentrations are higher than postpartum.

The Effect of Bariatric Surgery on the Relation Between Retinol-Binding Protein 4 (RBP4) and Vitamin D Plasma Levels in Male Obese Population.

Objectives Obesity is viewed as a risk factor for several life-threatening diseases. Bariatric surgeries are regarded as a safe and effective way of treating morbid obesity and are associated with alterations in molecules such as Vitamin D and retinol-binding protein 4 (RBP4). The aim of this study was to examine an association between Vitamin D and RBP4 in healthy obese individuals undergoing gastric sleeve surgery. Methods In this observational retrospective cohort study, we used clinical and biochemical profiles of morbidly obese healthy male subjects (BMI > 38.3) who underwent laparoscopic sleeve gastrectomy. RBP4 levels were evaluated by ELISA before and 6-12 months after surgery. Data were analysed using SPSS 23 statistical software. Results RBP4/Vitamin D ratio was reduced significantly after surgery (p < 0.001), however, there was no correlation between Vitamin D and RBP4 (p = 0.353). BMI was reduced significantly after surgery (p < 0.001) but was not correlated with RBP4 or Vitamin D levels before and after surgery (p > 0.05). A significant increase in the levels of calcium post-surgery was observed (p< 0.001). Conclusions In conclusion, plasma levels of Vitamin D were not correlated with RBP4 before or after laparoscopic gastric sleeve surgery.

The Effect of RBP4 on microRNA Expression Profiles in Porcine Granulosa Cells.

Retinol binding protein 4 (RBP4) is a transporter of vitamin A that is secreted mainly by hepatocytes and adipocytes. It affects diverse pathophysiological processes, such as obesity, insulin resistance, and cardiovascular diseases. MicroRNAs (miRNAs) have been reported to play indispensable roles in regulating various developmental processes via the post-transcriptional repression of target genes in mammals. However, the functional link between RBP4 and changes in miRNA expression in porcine granulosa cells (GCs) remains to be investigated. To examine how increased expression of RBP4 affects miRNA expression, porcine GCs were infected with RBP4-targeted lentivirus for 72 h, and whole-genome miRNA profiling (miRNA sequencing) was performed. The sequencing data were validated using real-time quantitative polymerase chain reaction (RT-qPCR) analysis. As a result, we obtained 2783 known and 776 novel miRNAs. In the experimental group, 10 and seven miRNAs were significantly downregulated and upregulated, respectively, compared with the control group. Ontology analysis of the biological processes of these miRNAs indicated their involvement in a variety of biological functions. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these miRNAs were involved mainly in the chemokine signaling pathway, peroxisome proliferators-activated receptors (PPAR) signaling pathway, insulin resistance pathway, nuclear factor-kappa B(NF-kappa B) signaling pathway, and steroid hormone biosynthesis. Our results indicate that RBP4 can regulate the expression of miRNAs in porcine GCs, with consequent physiological effects. In summary, this study profiling miRNA expression in RBP4-overexpressing porcine GCs provides an important reference point for future studies on the regulatory roles of miRNAs in the porcine reproductive system.

Serum retinol-binding protein 4 levels in polycystic ovary syndrome.

OBJECTIVE: Serum levels of retinol-binding protein 4 (RBP4), an adipokine thought to affect systemic insulin sensitivity, were compared between women with polycystic ovary syndrome (PCOS) and non-PCOS controls to evaluate the association of RBP4 with clinical, hormonal and metabolic parameters of PCOS. SUBJECTS AND METHODS: Serum RBP4 levels were analysed in 278 women with PCOS (age range 18-57 years) and 191 non-PCOS controls (age 20-53 years) by enzyme-linked immunosorbent assay. RESULTS: Serum levels of RBP4 were increased in women with PCOS compared with control women in the whole population (45.1 ± 24.0 (s.d.) vs 33.5 ± 18.3 mg/L, P < 0.001). Age-stratified analysis showed that serum RBP4 levels were increased in women with PCOS aged ≤30 years compared with controls (47.7 ± 23.5 vs 27.1 ± 10.4 mg/L, P < 0.001), whereas no significant differences were seen in the other age groups. No significant correlations of RBP4 were seen with either steroids or indices of insulin resistance. CONCLUSIONS: Although serum RBP4 levels were increased in younger women with PCOS compared with age-matched non-PCOS controls, RBP4 does not seem to be a good marker of insulin resistance or other metabolic derangements in women with PCOS.

Retinol-binding protein 4 is closely correlated to blood pressure level and E/A in untreated essential hypertension patients.

BACKGROUND: Hypertension, a common chronic disease, is a leading cause of death and other cardiovascular diseases. Recent studies show that an inflammatory factor named retinol binding protein 4 (RBP4) was increased with cardiovascular diseases. However, the relationship between RBP4 and hypertension in patients remains unclear. METHODS: The study cohort was composed of patients with essential hypertension (EH) and healthy control (HC) subjects from the Second Affiliated Hospital of Nanjing Medical University [2017-2019]. The levels of RBP4 and echocardiography were compared in the current study. Statistical differences between two groups were analyzed using unpaired Student's t-tests and the correlation between the two variables adopts Pearson correlation analysis. SPSS 23.0 was used for all statistical analysis. RESULTS: Analysis of patient plasma samples revealed that RBP4 in EH group was greater than HC group (P<0.05). The area under the ROC curve was 0.717. Specificity and sensitivity were 80.4% and 60.8%, respectively. RBP4 had positive correlation with left ventricular systolic diameter (LVDs), interventricular septal thickness (IVS) and left ventricular posterior wall thickness (LVPW), negative correlation with left ventricular shortening fraction (FS) and ejection fraction (EF) (P<0.05), and no correlation with left ventricular end-diastolic diameter (LVDd) (P>0.05). RBP4 was closely related with E/A, evaluation method of left ventricular diastolic function, in patients with EH. CONCLUSIONS: RBP4 levels are closely correlated with blood pressure (BP) levels and might be involved in the regulation of left ventricular diastolic function in patients with EH.

Transcriptomic Analysis of Porcine Granulosa Cells Overexpressing Retinol Binding Protein 4.

Retinol binding protein 4 (RBP4), mainly secreted by the liver and adipocytes, is a transporter of vitamin A. RBP4 has been shown to be involved in several pathophysiological processes, such as obesity, insulin resistance, and cardiovascular risk. Reports have indicated the high expression levels of RBP4 in cystic follicles. However, the role of RBP4 in mammalian follicular granulosa cells (GCs) remains largely unknown. To illustrate the molecular pathways associated with the effects of RBP4 on GCs, we used high-throughput sequencing to detect differential gene expression in GCs overexpressing RBP4. A total of 113 differentially expressed genes (DEGs) were identified in RBP4-overexpressing GCs, and they included 71 upregulated and 42 downregulated genes. The differential expressions of the top 10 DEGs were further confirmed by real-time quantitative polymerase chain reaction. Pathway analysis indicated that the DEGs are mostly involved in oxidative phosphorylation, Parkinson's disease, non-alcoholic fatty liver disease, Huntington's disease, cardiac muscle contraction, Alzheimer's disease, fatty acid biosynthesis, AMP-activated protein kinase signaling pathway, and insulin signaling pathway. Genes in these pathways should be useful for future studies on GCs. Altogether, the results of our study establish a framework for understanding the potential functions of RBP4 in porcine GCs.

Plasma retinol-binding protein-4 and tumor necrosis factor-α are reduced in postmenopausal women after combination of different intensities of circuit resistance training and Zataria supplementation.

PURPOSE: Zataria is a plant with anti-inflammatory properties, which has been used for the treatment of many diseases. This study investigated the effect of different intensities of circuit resistance training and Zataria supplementation on plasma retinol-binding protein-4 (RBP-4) and tumor necrosis factor-α (TNF-α) in postmenopausal women. METHODS: Seventy-two postmenopausal women were divided on randomized order into six groups: Control (McGinley and Bishop in J Appl Physiol 121(6):1290-1305, 2016), Training 35% (T35%), Training 55% (T55%), Zataria (Özgünen et al. in Scand J Med Sci Sports 20:140-147, 2010), Zataria/Training 35% (ZT35%), and Zataria/Training 55% (ZT55%). Resist-ance training program included 12 exercise stations (each: 30 s, intensity: 35% and 55% of 1-RM) for 8 weeks (3 sessions/week). Daily (500 mg) Zataria was used after breakfast by participants in ZG, ZT35%, and ZT55% groups. Blood samples were taken 48 h before and after the first and last sessions of training. RESULTS: After the training period the percentage of body fat decreased significantly (P < 0.001) in all trained groups, whereas muscle mass increased significantly (P < 0.01) only in T55% and ZT55% groups. A significant decrease was observed for RBP-4 values (P < 0.05) after training in all groups except for ZG and CG. Also, RBP-4 was significantly lower (P < 0.05) in all groups as compared to CG at the post-test except for ZG. Moreover, significantly lower values (P < 0.05) were found in T55%, ZT35%, and ZT55% as compared to ZG in post-intervention. TNF-α values decreased significantly (P < 0.05) at the post-test as compared to pre-intervention in ZT35% and ZT55%. Also, TNF-α was significantly lower (P < 0.05) in ZT55% compared to CG and T35% in post-test. CONCLUSIONS: The results demonstrate clearly that in postmenopausal women, circuit resistance training both at low and moderate intensities cause a greater reduction in RBP-4 and TNF-α when Zataria is supplemented in the diet during training.

Association of RBP4 gene variants with adverse lipid profile and obesity.

Obesity is currently a worldwide public health problem. Retinol-binding protein4 (RBP4) is a recently discovered adipokine, which is potentially associated with insulin resistance and obesity. We aimed to investigate whether genetic variation within the RBP4 gene is correlated with the obesity and lipid profile in Iranian population. 321 samples were randomly selected from participants of Isfahan Healthy Heart Program (IHHP). Genomic DNA was isolated from peripheral blood cells (PBCs) and HRM-PCR was performed in order to investigate the presence of SNPs, and further sequencing analysis was done from selected subjects according to the differences of HRM curve pattern. Statistical analyses were performed using SPSS v16.00. The difference of the presence of rs3758539 polymorphism between controls and obese patients was significant, but not about rs10882280. We found noticeable association among genetic polymorphisms and biomedical and physical characteristics within investigated population. Our findings suggested that variations in the RBP4 gene were correlated with BMI and polymorphisms more likely could contribute to the development of obesity in our population. Also appraisal of obesity risk factors within each group might be helpful for preventing obesity initiation and could have a possible role in a predisposition to obesity in the Iranians.

Differences in Adipokine and Hepatokine Levels among Non-diabetic Population Classified by Age and Sex.

BACKGROUND: Leptin, angiopoietin-related growth factor (AGF), adiponectin (ADP), and retinol-binding protein 4 (RBP4) are cytokines associated with the development of metabolic disorders, such as type 2 diabetes and cardio vascular disease. However, the levels of these cytokines have not extensively studied in non-diabetic subjects. Therefore, we analyzed the differences in these cytokine levels according to sex and age in non-diabetic Korean population. METHODS: Blood samples were collected from 59 non-diabetic Korean adults (male, 32; female, 27). The anthropometric and biochemical data were measured at the health examination center. Serum adipokines and hepatokines were measured by enzyme linked immunosorbent assay (ELISA). The data were analyzed according to sex and age-based quartiles. RESULTS: Serum leptin values were higher in females (8.60 ± 3 µg/ml) compared with males (2.99 ± 2.9 µg/ml). However, RBP4 was higher in males (84.05 ± 47.04 µg/ml) than in females (61.25 ± 45.42 µg/ml). The AGF and ADP values were not significantly different between males and females. RBP4 level was inversely correlated with age quartile in males, while leptin was significantly associated with body mass index and insulin resistance. CONCLUSION: RBP4 and AGF levels showed age-associated change, and leptin was consistently higher in females. Therefore, a large-scale analysis to determine the normal range of adipokines and hepatokines concentration in healthy Korean population is necessary. When interpreting adipokine and hepatokine levels, the difference in age and sex needs to be taken into account.

The tumor necrosis factor-?inhibits retinol binding protein 4 secretion in mature 3T3-L1 adipocytes / 重庆医科大学学报

Objective:To explore the effects of tumor necrosis factor-?(TNF-?) on retinol binding protein 4 (RBP4) secreted by mature 3T3-L1 adipocytes in-vitro.Methods:3T3-L1 preadipocytes were cultured and differentiated into the mature adipocytes after 2 days of confluenence.Recombinant TNF-?at different concentrations was added to the culture medium of fully differentiated adipocytes.Total protein of RBP4 secreted by these adipocytes was evaluated by radioimmunoassay(RIA) at various times.Results:(1)Treatment of mature 3T3-L1 adipocytes with TNF-?at different concentrations (0.2,1.0,5.0, 10ng/ml) decreased RBP4 secretion.The inhibitive effect of TNF-?on RBP4 was in dose dependent manner.The level of RBP4 decreased along with the elevated TNF-?concentration in the culture medium.(2)Almost the RBP4 secretion in all experiment groups had a decreasing tread at different time points,but there was no statistical difference in each group.(3) Regression analysis indicated TNF-?had significant associations with RBP4.Conclusion:TNF-?inhibits mature adipocytes RBP4 secretion in-vitro in dose-response effects,but there is no time-response effects.