Circulating Retinol Binding Protein 4 Levels Research Articles

Retinol-binding protein 4 (RBP4) circulating levels and gestational diabetes mellitus: a systematic review and meta-analysis.

Gestational diabetes mellitus (GDM) is a prevalent condition where diabetes is diagnosed during pregnancy, affecting both maternal and fetal outcomes. Retinol-binding protein 4 (RBP4) is a circulating adipokine which belongs to the lipocalin family and acts as a specific carrier protein that delivers retinol (vitamin A) from the liver to the peripheral tissues. Growing data indicate that circulating RBP4 levels may positively correlate with GDM. Thus, this systematic review and meta-analysis aimed to investigate the potential relationship between circulating RBP4 levels and GDM when measured at various stages of pregnancy. MEDLINE, CINAHL, EMCARE, EMBASE, Scopus, and Web of Science databases were searched to identify studies comparing pregnant women with and without GDM, whose circulating RBP4 levels were measured in at least one pregnancy trimester. Findings were reported using standardized mean difference (SMD) and random-effects models were used to account for variability among studies. Furthermore, the risk of bias was assessed using the RoBANS tool. Out of the 34 studies identified, 32 were included in the meta-analysis (seven with circulating RBP4 levels measured in the first trimester, 19 at 24-28 weeks, and 14 at >28 weeks of pregnancy). RBP4 levels were statistically higher in the GDM group than in controls when measured during all these pregnancy stages, with the noted RBP4 SMD being 0.322 in the first trimester (95% CI: 0.126-0.517; p < 0.001; 946 GDM cases vs. 1701 non-GDM controls); 0.628 at 24-28 weeks of gestation (95% CI: 0.290-0.966; p < 0.001; 1776 GDM cases vs. 1942 controls); and 0.875 at >28 weeks of gestation (95% CI: 0.252-1.498; p = 0.006; 870 GDM cases vs. 1942 non-GDM controls). Significant study heterogeneity was noted for all three pregnancy timepoints. The present findings indicate consistently higher circulating RBP4 levels in GDM cases compared to non-GDM controls, suggesting the potential relevance of RBP4 as a biomarker for GDM. However, the documented substantial study heterogeneity, alongside imprecision in effect estimates, underscores the need for further research and standardization of measurement methods to elucidate whether RBP4 can be utilized in clinical practice as a potential GDM biomarker. PROSPERO (CRD42022340097: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022340097).

Retinol-Binding Protein 4 and Visfatin Levels in Patients with Periodontitis and Obesity/Overweight: A Systematic Review and Meta-Analysis.

Prior studies demonstrated an equivocal conclusion about the association between the level of retinol-binding protein 4 (RBP4)/visfatin and periodontitis patients with obesity. The aim of our study (Prospero ID: CRD42023469058) was to systematically review the available articles linking the biofluid levels of RBP4/visfatin to the comorbidity of periodontitis and obesity. Clinical trials were screened in accordance with specific inclusion criteria from seven databases up to November 2023. A quality assessment was performed with the Newcastle-Ottawa Scale and ROBINS-I tools for observational and interventional trials, respectively. The standard mean difference (SMD) with a 95% confidence interval (CI) related to the RBP4 level was recorded; the other indicators related to the visfatin level were measured via the mean difference (MD) with the corresponding 95% CI, and Fisher's Z transformation was measured to reveal the association using Review Manager 5.4. The current evidence was based on five observational studies and two interventional studies. All of them were included in the systematic review, and six of them were in the meta-analysis. Statistical analysis indicated that there was no significant difference in the circulating levels of RBP4 in the periodontitis patients with obesity or without, who were labeled as OP or NP, respectively (155 OP-107 NP: SMD = 1.38; 95% CI: -0.18-2.94, p = 0.08), as well as the periodontal healthy patients with a normal weight, who were labelled as NnP (116 OP-79 NnP: SMD = 6.76; 95% CI: -5.34-18.87, p = 0.27). Meanwhile, a significant higher level of serum visfatin was found in the OP patients than that of the NP (86 OP-45 NP: MD = 4.21; 95% CI: 2.65-5.77, p < 0.00001)/NnP (164 OP-88 NnP: MD = 13.02; 95% CI: 7.34-18.70, p < 0.00001) group. In addition, a positive association was observed between the serum RBP4 and body mass index/clinical attachment loss (CAL). And, then, there was a positive association between the serum visfatin and periodontal parameters, including the probing depth, CAL, and plaque index, as well as metabolic parameters, including the total cholesterol, triglycerides, fasting blood glucose, and low-density lipoprotein cholesterol. Here, the circulating RBP4 level was not independently related to the comorbidity of periodontitis and obesity, while serum visfatin was significantly associated with periodontitis and obesity. Notably, the positive association between circulating RBP4/visfatin and the periodontal parameters/metabolic parameters firmly suggested that the higher severity of the obese or periodontal status was associated with an elevated level of serum visfatin or RBP4 in the OP group. With more rigorous longitudinal research, the exact causations between RBP4/visfatin and the patients affected by obesity and periodontitis could be disentangled. RBP4 and visfatin might be novel, enlightening prospective bio-indexes for the targeted treatment of comorbidities.

Assessment of Circulating Retinol Binding Protein-4 Levels in Patients with Compound Heterozygosity for Hb S and β-Thalassemia

Background: Retinol Binding Protein-4 (RBP-4) is a member of the lipocalin family of proteins and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body's vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP-4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP-4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. While, after its dissociation from TTR and retinol release, retinol-free apo-RBP4 in the circulation is filtrated by the kidney. More than 99% of that is reabsorbed by the proximal renal tubule, which renders urinary RBP-4 a highly sensitive marker for tubular dysfunction. We and other have shown previously that the patients with Sickle Cell Disease (SCD) have deficiencies or suboptimal levels of vitamin A, while recently (Br J Haematol. 2023;doi:10.1111/bjh.18862) higher urine RBP-4 in patients with SCD especially in those with persistent albuminuria but without an association of urine RBP-4 levels with estimated glomerular filtration rate (eGFR). In this context, we aimed to investigate the potential clinical significance of circulating plasma RBP-4 levels and its association with disease features in Caucasian patients with compound heterozygosity for HbS and β-thalassemia (HbS/β thal). Patients and Methods: Ninety Caucasian adult patients with HbS/β thal at steady phase were included in the study, while 22 apparently healthy individuals of similar age and gender served as controls. None of the patients was diabetic and has received any transfusions at least 6-monthes before enrollment in the study. RBP-4 concentration was measured with an immunoturbidimetric assay applied in an automated chemistry analyzer, along with hematologic, and series of blood chemistry parameters reflecting renal, cardiac and endothelial dysfunction. eGFR values were calculated using the CKD-EPI (Cystatin C and/or Creatinine equations). Results: We found that: a) Plasma RBP-4 levels were significantly lower in patients with HbS/β thal compared to controls, 30.5±2.7mg/L (Confidence Intervals (CI): 28.8;32.2mg/mL) vs 36.3±3.6mg/L (CI: 32.7;39.9mg/mL), p&amp;lt;0.003. The patients with β + genotypehave higher RBP-4 levels than those with β 0 genotype (p&amp;lt;0.05), whereas patients treated with hydroxycarbamide(50/90) are more likely to express higher RBP-4 levels, p-trend=0.06; b) RBP-4 levels in patients with HbS/β thal correlated positively with their age, body mass index (BMI) and Hb levels (r=0.264, p=0.012; r=0.334, p=0.001 and r=0.209, p&amp;lt;0.05, respectively; c) RBP-4 levels in patients with HbS/β thal correlated with total bilirubin, total cholesterol, triglycerides and uric acid (r=-0.452, p&amp;lt;0.001; r=0.395, p=0.004; r=0.292, p=0.015 and r=0.435, p&amp;lt;0.001, respectively); d) RBP-4 levels in patients with HbS/β thal correlated negatively with eGFR values rho=-0.360, p=0.003 and hs-CRP concentrations r=-0.309, p=0.004 and e) No correlations were found between RBP-4 levels with markers of cardiac and endothelial dysfunction such as High Sensitivity Troponin T, Growth Differentiation Factor-15, von Willebrand factor antigen, Α Disintegrin and Metalloproteinase with Thrombospondin Type 1 Motif 13 antigen and P-Selectin, as well as with number of vaso-occlusive crisis and mean pulmonary arterial pressure in the patients. Conclusions: These findings demonstrate a multifactorial role of RBP-4 in patients with HbS/β thal as the circulating levels of the protein correlate significantly with markers of erythropoiesis, inflammation and renal function. It is unclear of this study if RBP-4 has any specific functions in patients with HbS/β thal. However, RBP-4 should be more investigated in order to determine its clinical significance and in the case of sickle cell nephropathy both plasma and urine measurements should be considered.

Association Between Circulating Retinol-Binding Protein 4 and Adverse Cardiovascular Events in Stable Coronary Artery Disease.

BackgroundThe predictive role of retinol-binding protein 4 (RBP4) in the adverse prognosis of patients with stable coronary artery disease (CAD) has not been well-defined. We thus conducted this cohort study to investigate the association between circulating RBP4 level and major adverse cardiovascular events (MACEs) in Chinese patients with stable CAD.MethodsPatients with stable CAD and serum RBP4 concentration measurement at admission between July 2012 and January 2015 were included. The primary outcome in this study was incident MACEs, which included acute coronary syndrome, heart failure, stroke, peripheral vascular disease, and cardiovascular death. Cox proportional hazards regression was adopted to investigate the association between RBP4 and the incidence of MACEs.ResultsA total of 840 patients with stable CAD were analyzed. The mean age of patients was 61.2 ± 15.9 years, and 56.1% of them were men. After a median follow-up of 2.3 years, 129 MACEs were observed. Compared to participants exposed to the first quartile of serum RBP4 level, those in the second, the third, and the fourth quartiles had associated hazard ratios (HRs) of 2.38 [95% confidence interval (CI): 1.33–4.26], 2.35 (95% CI: 1.31–4.21), and 2.27 (95% CI: 1.28–4.04) after adjusted for confounders, respectively. Every 5 μg/ml increment in serum RBP4 concentration was associated with an adjusted HR of 1.13 (95% CI: 1.05–1.22) for the occurrence of MACEs. Subgroup analyses suggested no significant modifying effects of baseline characteristics for the association between RBP4 and MACEs in patients with stable CAD.ConclusionOur finding suggested that the higher circulating RBP4 level was significantly associated with an increased risk of MACEs in patients with stable CAD.

Retinol-Binding Protein 4 Activates STRA6, Provoking Pancreatic β-Cell Dysfunction in Type 2 Diabetes.

Pancreatic β-cell dysfunction plays a decisive role in the progression of type 2 diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes, although its effect on β-cell function remains elusive, and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic β-cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose-stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4 transgenic (RBP4-Tg) overexpressing mice showed a dynamic decrease of GSIS, which appeared as early as 8 weeks old, preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6 (STRA6), RBP4's only known specific membrane receptor, is expressed in β-cells and mediates the inhibitory effect of RBP4 on insulin synthesis through the Janus kinase 2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore β-cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic β-cell dysfunction, which provides new insight into the diabetogenic effect of RBP4.

Circulating Retinol-Binding Protein 4 Is Inversely Associated With Pancreatic β-Cell Function Across the Spectrum of Glycemia.

The aim of this study was to examine the association of circulating retinol-binding protein 4 (RBP4) levels with β-cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. A total of 291 subjects aged 35-60 years with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT), or type 2 diabetes were screened by a standard 2-h oral glucose tolerance test (OGTT) with the use of traditional measures to evaluate β-cell function. From these participants, 74 subjects were recruited for an oral minimal model test, and β-cell function was assessed with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. Circulating RBP4 levels were significantly and inversely correlated with β-cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indices, but not with HOMA of β-cell function, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β-cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion. Circulating RBP4 levels are inversely and independently correlated with β-cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.

Changes of serum retinol-binding protein 4 associated with improved insulin resistance after laparoscopic sleeve gastrectomy in Chinese obese patients

BackgroundSerum retinol-binding protein 4 (RBP4) plays a critical role in insulin resistance. The mechanism behind the impact of laparoscopic sleeve gastrectomy (LSG) on glucose metabolism is unclear. Hence, we aimed to investigate the triangle relationship between the RBP4, glucose metabolism, and LSG in patients of Chinese ethnicity.MethodsThe study enrolled eighty-two obese patients. Glucose-lipid metabolic index, uric acid (UA), superoxide dismutase (SOD), free triiodothyronine (FT3), free thyroxin (FT4) and thyrotropin (TSH) were measured. RBP4 levels were detected by enzyme-link immunosorbent assay. 30 obese patients underwent LSG were studied. All these markers were measured again at a time interval of 3 and 6 months after surgery.Results(1) Circulating RBP4 levels were positively associated with body mass index(BMI), blood glucose in 0 min (BG0), BG30, BG120, BG180, fasting inulin(FINS), fasting C peptide(FCP), homeostasis model of assessment for insulin resistance index (HOMA-IR), SOD, TSH and negatively associated with Matsuda index in obesity with a significant difference (P < 0.05). RBP4 levels in the patients with impaired fasting glucose (IFG), insulin resistance or hyperinsulinemia were significantly higher than the patients without IFG, insulin resistance or hyperinsulinemia (P = 0.035, P = 0.001, and P = 0.007). (2) LSG resulted in significantly decreased FBG, FINS, FCP and HOMA-IR at 3, 6 months after surgery (all P < 0.05). The RBP4 levels were significantly decreased after surgery (all P < 0.05) with no gender difference. (3) The change in RBP4 levels was significantly associated with the change in FINS, FCP, HOMA-IR, and HOMA-β at 6 months and the change in TSH at 3 months after surgery in males (all P < 0.05). The change in RBP4 levels were significantly associated with the change in FINS, FCP, HOMA-IR, HOMA-β, and TCH at 3 months after surgery in females (all P < 0.05).ConclusionsOverall, our results interpret the significant correlations between RBP4, glucose-lipid metabolism, oxidative stress and thyroid function in obese patients. Further, the LSG brings a decline in RBP4 levels and that may contribute partly to the improved insulin resistance in obese Chinese patients.

Impact of Gastric Sleeve Surgery on Plasma Retinol Binding Protein 4 and Adipsin Levels in Healthy Male Population.

Objectives:Bariatric surgery provides most substantial and sustainable weight loss measures in individuals with obesity. Caloric restriction is not only intervention, changes in hormonal secretions are also leading contributory mechanisms to reduce body weight and improve the glycaemic control. The aim of this study was to evaluate the impact of gastric sleeve surgery on plasma retinol binding protein 4 (RBP4) and adipsin levels among Saudi male obese population.Methods:This prospective study was conducted in the Departments of Physiology and Surgery, College of Medicine, King Saud University. Thirty-three obese (BMI>38.3) male patients age ranged from 25 to 50 years were recruited. RBP4 and adipsin levels were analyzed before and 6-12 months after gastric sleeve surgery by ELISA along with plasma glucose, insulin, HOMA-IR and lipid profile.Results:Circulating RBP4 levels were not significantly changed by bariatric surgery (4382.85±40.35 ng before, and 4393.28±33.13 ng after surgery, p=0.842), neither did adipsin (2949.68±46.86 pg before, and 2917.90±41.90 pg after surgery, p=0.535). Segregation of study participants into two age groups, 25-35 and 35-50 years of age, revealed that before surgery older age group (35-50) had higher RBP4 levels compared to younger group (25-35) (p=0.016). However, after surgery RBP4 levels were decreased in older group but not to a significant level (p=0.174). In younger age group after surgery, there was a near significant increase in RBP4 levels (p=0.052). There were no significant changes in RBP4 levels in both age groups after surgery (p=0.461). For adipsin, there were no significant differences before and after surgery in both age groups. Insulin, BMI and HOMA-IR index were decreased after surgery, however there was no correlation with RBP4 and adipsin levels.Conclusions:The present study findings do not suggest a role for RBP4 and adipsin in the improvement of insulin sensitivity in Saudi male obese population after gastric sleeve surgery. However, a decrease in RBP4 levels in older individuals after surgery needs further investigations to understand its effect on weight and glycemic control.

Retinol binding protein 4 abundance in plasma and tissues is related to body fat deposition in cattle

Retinol binding protein 4 (RBP4) facilitates the transport of retinol in the body but is also an adipokine and fatty acid transporter. Our study was aimed at investigating the associations between RBP4 abundance and fat deposition in cattle. Blood samples of 246 crossbred bulls were taken at 8 months of age and at slaughter at 18 months of age for the determination of RBP4, hormone levels, and fatty acid composition. Significant correlations between plasma RBP4 abundance at 8 months of age and carcass traits at 18 months of age were detected (e.g., r = 0.3; P < 0.001 to carcass fat). Furthermore, RBP4 abundances in the plasma and subcutaneous fat were higher (P < 0.05) in bulls with increased fat deposition, whereas the liver RBP4 expression was not (P > 0.05). Retinol binding protein 4 was immunohistochemically localized in or close to adipocytes within muscle and adipose tissue and in liver stellate cells but not in hepatocytes. Overall, our results indicate that increased RBP4 levels were associated with increased fat deposition and altered fatty acid composition, but not with altered glucose tolerance, in crossbred bulls. Moreover, our results suggest that adipose-tissue-derived RBP4 may contribute to the circulating RBP4 level.

Sexual dimorphism in developmental and diet-dependent circulating retinol binding protein 4.

SummaryObjectiveRetinol binding protein 4 (RBP4) transports vitamin A (Retinol) in the blood and contributes mechanistically to the linkage between obesity, insulin resistance and associated comorbidities including type 2 diabetes mellitus, coronary artery and neoplastic diseases. Circulating RBP4 levels have variably been associated with body mass and gender differences. Many of these differences have been demonstrated after limited dietary interventions, and/or at single unique time points. This study investigated the impact of sex and age as biologic variables as well as high versus low fat diets on development of obesity, RBP4 levels and insulin resistance in C57BL/6J mice.MethodsMale and female C57BL/6J mice were fed for 400 days with either low or high fat diets. Female mice were also evaluated on same diets after ovariectomy or sham ovariectomy. Mice were monitored for changes in weight, circulating levels RBP4, glucose and insulin at 100‐day intervals and also by 2‐hour glucose tolerance tests.ResultsAll mice on low or high fat diets gained weight. Mice on high fat diets showed significantly greater weight gain than those on low fat. Male mice showed significantly greater weight gain compared with females on corresponding diet. Male mice compared with females already showed significantly higher RBP4 levels even before starting diets. Sex differences were maintained for more than 1 year. Gender differences in RBP4 were associated with significant differences in development of glucose intolerance and insulin resistance.ConclusionsMale compared with female C57BL/6J mice show significant gender differences in circulating RBP4 levels from 6 weeks of age, extending more than 1 year. Gender differences in RBP4 may be mechanistically associated with protection against glucose intolerance and insulin resistance. Targeting RBP4 pathways could be useful to disrupt gender differences in insulin resistance and disparities in comorbidities.

Plasma concentration of Retinol Binding Protein 4 (RBP4) in relation to nutritional status and kidney function in older population of PolSenior Study

PurposeThe aim of the study was to assess plasma RBP4 concentration in elderly subjects in relation to nutritional status and kidney function in the population of the PolSenior Study. Material and methodsWe assessed RBP4, glucose, insulin, albumin, lipid profile, C-reactive protein, (hsCRP) and creatinine concentrations in 2614 PolSenior Study participants (1235 women and 1379 men). The study group was divided based on BMI and HOMA-IR values, and the occurrence of diabetes. ResultsPlasma RBP4 concentration was similar in normal weight, overweight, and obese subgroups, both in women (40.4 vs 40.8 vs 41.8 ng/ml, respectively), and men (41.2 vs 40.3 vs 42.9 ng/ml, respectively). Similar values were found in subjects with HOMA-IR <2.5; ≥2.5 and diabetes, while those with decreased eGFR (<60 ml/min/1.73 m2) were characterized by increased RBP4 levels [46.0 (32.0–64.8) vs 39.4 (28.2–54.9) ng/ml; p < 0.001]. Plasma RBP4 level variability was explained by: age, waist circumference or BMI, and eGFR, but not HOMA-IR and/or hsCRP. The standardized coefficients β (slopes) for BMI and waist circumference were similar. ConclusionsThe results revealed that in older subjects, circulating RBP4 levels are mostly affected by kidney function and modestly by age, gender, and nutritional status, but not insulin resistance.

Effects of insulin resistance on the association between the circulating retinol-binding protein 4 level and clustering of pediatric cardiometabolic risk factors.

Retinol-binding protein 4 (RBP4) and insulin resistance (IR) are clinical parameters associated with cardiometabolic diseases. The mediating and modifying roles of IR on children's susceptibility to cardiometabolic disorders are undetermined. This study investigated the mediating and modifying effects of the homeostatic model assessment of IR (HOMA-IR) on the relationship between the serum RBP4 level and clustering of pediatric cardiometabolic risk factors. We assessed the diet, physical activity, cardiometabolic risk factors, and clinical parameters of 272 randomly selected adolescents from a large-scale cross-sectional study (n = 2727). Two HOMA-IRs (HOMA1-IR and HOMA2-IR) were used to evaluate the designated effects. Levels of serum RBP4 positively correlated with the levels of the 2 HOMA-based-IRs, and HOMA-IR correlated to all components of pediatric metabolic syndrome (MetS), the number of abnormal components, and a body-weight-weighted principal component score extracted from 12 cardiometabolic risk factors. Increased RBP4 levels had positive effects on waist circumference (WC), triglyceride, and the number of abnormal MetS components (0.310 cm, 1.384 μg/dL, and 0.021 item elevations, respectively), and the HOMA-IRs explained 17.7% to 21.9%, 11.8% to 27.6%, and 23.8% to 25.0% of these effects. The association of WC and the number of abnormal MetS components with the serum RBP4 level was enhanced by higher HOMA-IR (β for interaction, 0.13 and 0.01 for HOMA1-IR, and 0.32 and 0.02 for HOMA2-IR, respectively). HOMA-IR is associated with the circulating RBP4 level and cardiometabolic risk factors in adolescents. Pediatric HOMA-IR may have mediating and modifying effects on the positive correlations between RBP4 and the clustering of MetS components.

Retinol-Binding Protein-Dependent Cholesterol Uptake Regulates Macrophage Foam Cell Formation and Promotes Atherosclerosis.

Retinol-binding protein 4 (RBP4) is an adipokine that plays decisive roles in glucose metabolism and insulin sensitivity. Elevated circulating RBP4 levels were reported to be associated with increased risk for cardiovascular disease, but the precise role of RBP4 in atherosclerotic diseases and its mechanisms of action remain elusive. Serum RBP4 levels of 1683 participants from South China were evaluated and the occurrence of major adverse cardiovascular events was followed up for 5 years. Apolipoprotein E-deficient mice infected with RBP4-overexpressing/silencing adenovirus, J774A.1 macrophages, and primary peritoneal macrophages from RBP4 transgenic mice were used for investigating the function of RBP4 in foam cell formation. Prospective cohort studies revealed that baseline serum RBP4 level was an independent predictor for incidence of adverse cardiovascular events after adjustment for traditional risk factors. Increased RBP4 expression was observed in atherosclerotic lesions of aortic specimens from both humans and apolipoprotein E-deficient mice, and RBP4 was localized to areas rich in macrophage foam cells. RBP4 inhibition attenuated whereas overexpression accelerated atherosclerosis progression in apolipoprotein E-deficient mice. Both treatment with exogenous recombinant RBP4 and overexpression of RBP4 gene promoted macrophage-derived foam cell formation through the activation of scavenger-receptor CD36-mediated cholesterol uptake, and RBP4 transcriptionally upregulated CD36 expression in a manner dependent on jun N-terminal kinase and signal transducer and activator of transcription 1. The tyrosine kinase c-Src was identified as the upstream regulator of jun N-terminal kinase-signal transducer and activator of transcription 1-mediated CD36-dependent cholesterol uptake, and RBP4 challenge was found to alter the membrane distribution of c-Src and cause c-Src to partition into lipid-raft membrane subdomains, where the kinase was activated. Lastly, Toll-like receptor 4, but not retinol or stimulated by retinoic acid 6, mediated the inductive effects of RBP4 in macrophages. Inclusion of RBP4 levels in traditional models enhances the predictive ability for the incidence of atherosclerotic events. RBP4 promotes atherogenesis by inducing macrophage-derived foam cell formation.

Serum levels of RBP4 might not be determined by diabetes mellitus but by kidney function and renal replacement therapy

It has been reported that retinol-binding protein 4 (RBP4) is associated to adiposity, insulin resistance, and type 2 diabetes. Meanwhile, circulating RBP4 levels are also affected by renal function. The aim of the present study is to investigate whether serum levels of RBP4 are primarily associated with different stages of chronic kidney disease (CKD) or type 2 diabetes, if there is more potential relevance between RBP4 and renal replacement therapy. The serum levels of RBP4 were assessed by commercial competitive enzyme-linked immunosorbent assay (ELISA) kit in 212 patients with the CKD stages 1—5 and in 24 healthy controls, while its correlation with clinical and metabolic parameters was analyzed. The serum level of RBP4 had a strong correlation with estimated glomerular filtration rate (eGFR) (P 0.05 for all]. The elevation of RBP4 become higher in HD than in PD and ND in CKD5 patients (P = 0.008 and P = 0.04, respectively), while there was no significant difference between PD and ND groups. Multivariate linear regression analysis demonstrated three independent predictors of eGFR (β = −0.676, P < 0.001), C-reactive protein (CRP) (β = −0.573, P < 0.001) and creatine (β = 0.509, P = 0.024) in the study population. The study results demonstrated that the serum level of RBP4 was negatively related to the eGFR, whether diabetes mellitus (DM) affected the blood concentration of RBP4 or not. And the serum level of RBP4 exhibited significant difference in different renal replacement therapies.

The relationship between retinol-binding protein-4 and cardiometabolic risk factors in obese patients with type 2 diabetes mellitus

Background: Retinol-binding protein-4 (RBP4) is an adipocyte-secreted hormone considered to link obesity with cardiovascular complications. The oxidative stress has been implicated in the pathophysiology of obesity. We evaluated serum RBP4 and plasma total thiols (TT) in generalized obesity (GO) and abdominal obesity (AO) in relationship to classical cardiovascular risk factors. Glycated haemoglobin (HbA1c%), C-reactive protein (CRP) and lipid profile were also evaluated. Patients and Methods: Sixty obese patients were recruited [30 abdominally obese (AO) patients, (15 male and 15 female, mean (SD), 49.5 (5.5) years) were measured by waist circumference (WC &gt; 102 cm for men or &gt; 88 cm for women) and waist/hip ratio (WC divided by that of the hips of &gt; 0.9 for men and &gt; 0.85 for women)] and [30 generalized obese (GO) patients (22 male and 8 female; mean (SD); 42.5 (8) years) were measured by body mass index (BMI). [BMI ≥ 30.0-34.9 kg/m2, with normal WC] compared to 20 healthy subjects (14 males and 6 females; mean age (SD); 36.60 (5.97) years). Results: AO had significantly higher circulating RBP4 levels in comparison to GO (p&lt; 0.05). Total thiols levels were significantly lower in AO compared to GO patients (p&lt; 0.05). CRP significantly elevated in AO compared to GO patients (p&lt;0.05). Total serum cholesterol, triglycerides and Hb1Ac% increased with BMI, WC and waist/hip ratio (WHR). Conclusion: The study reveals that RBP4 is autonomously related to visceral fat accumulations and cardiovascular diseases. The study also reveals the beneficial effect of TT against obesity and cardiovascular disease and the potential clinical applicability of RBP4 and total thiols in cardiovascular diseases.

Elevated Serum Triglyceride and Retinol-Binding Protein 4 Levels Associated with Fructose-Sweetened Beverages in Adolescents

BackgroundThe metabolic effect of fructose in sugar-sweetened beverages (SSB) has been linked to de novo lipogenesis and uric acid (UA) production.ObjectivesThis study investigated the biological effects of SSB consumption on serum lipid profiles and retinol-binding protein 4 (RBP4) among Taiwanese adolescents.MethodsWe evaluated the anthropometric parameters and biochemical outcomes of 200 representative adolescents (98 boys and 102 girls) who were randomly selected from a large-scale cross-sectional study. Data were analyzed using multiple regression models adjusted for covariates.ResultsIncreased SSB consumption was associated with increased waist and hip circumferences, body mass index (BMI) values and serum UA, triglyceride (TG) and RBP4 levels. Adolescents who consumed >500 ml/day of beverages half-to-heavily sweetened with high-fructose corn syrup (HFCS) exhibited TG and RBP4 levels 22.7 mg/dl and 13.92 ng/ml higher than non-drinkers, respectively. HFCS drinkers with hyperuricemia had higher TG levels than HFCS drinkers with normal UA levels (98.6 vs. 81.6 mg/dl). The intake of HFCS-rich SSBs and high value of BMI (≥24) interactively reinforced RBP4 levels among overweight/obese adolescents. Circulating RBP4 levels were significantly correlated with weight-related outcomes and TG and UA concentration among HFCS drinkers (r = 0.253 to 0.404), but not among non-drinkers.ConclusionsHigh-quantity HFCS-rich beverage consumption is associated with higher TG and RBP4 levels. Hyperuricemia is likely to intensify the influence of HFCS-rich SSB intake on elevated TG levels, and in overweight and obese adolescents, high BMI may modify the action of fructose on higher circulating levels of RBP4.

Association between retinol-binding protein 4 and polycystic ovary syndrome: A meta-analysis

Studies have examined the association between retinol-binding protein 4 (RBP4) and polycystic ovary syndrome (PCOS). However, the results have been inconsistent. To investigate the association between RBP4 and PCOS, we performed a meta-analysis. The Cochrane Library, MEDLINE, the ISI Web of Science, and EMBASE were searched to identify all of the studies that examined the relationship between circulating RBP4 levels and PCOS. Standard mean difference (SMD) values and 95% confidence interval (CI) were estimated and pooled using meta-analysis methodology. A total of seven studies were involved in the meta-analysis, which included a total of 636 subjects (260 controls and 376 patients with PCOS). The RBP4 level was higher in PCOS patients than in non-PCOS patients (random effects MD (95% CI)=0.69, [0.20, 1.18], P=0.006). However, the RBP4 level was not higher in nonobese PCOS patients than in nonobese controls (random effects MD (95% CI)=0.38, [-0.21, 0.98], P=0.20). The effect size revealed that the RBP4 level was higher in overweight or obese PCOS patients than weight-matched controls (fixed effects MD (95% CI)=7.95, [5.96, 9.93], P<0.05). In the subgroup analysis by region, the RBP4 level was higher in PCOS patients in Asia than controls (random effects MD (95% CI)=0.85, [0.54, 1.15], P<0.05), but not in European PCOS patients compared with controls (random effects MD (95% CI)=0.34, [-1.12, 1.80], P=0.65). This subgroup analysis also showed that nonobese PCOS patients have higher RBP4 levels than controls in Asia. Our meta-analysis results indicated that RBP4 might be a useful tool for identifying PCOS women.

Ghrelin- and GH-induced insulin resistance: no association with retinol-binding protein-4

ObjectiveSupraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects.Materials and methodsTo study GH-independent effects of ghrelin, seven hypopituitary men undergoing replacement therapy with GH and hydrocortisone were given ghrelin (5 pmol/kg per min) and saline infusions for 300 min in a randomized, double-blind, placebo-controlled, crossover design. Circulating RBP4 levels were measured at baseline and during a hyperinsulinemic–euglycemic clamp on both study days. To study the direct effects of GH, nine healthy men were treated with GH (2 mg at 2200 h) and placebo for 8 days in a randomized, double-blind, placebo-controlled, crossover study. Serum RBP4 levels were measured before and after treatment, and insulin sensitivity was measured by the hyperinsulinemic–euglycemic clamp technique.ResultsGhrelin acutely decreased peripheral insulin sensitivity. Serum RBP4 concentrations decreased in response to insulin infusion during the saline experiment (mg/l): 43.2±4.3 (baseline) vs 40.4±4.2 (clamp), P<0.001, but this effect was abrogated during ghrelin infusion (mg/l): 42.4±4.5 (baseline) vs 42.9±4.7 (clamp), P=0.73. In healthy subjects, serum RBP4 levels were not affected by GH administration (mg/l): 41.7±4.1 (GH) vs 43.8±4.6 (saline), P=0.09, although GH induced insulin resistance.Conclusionsi) Serum RBP4 concentrations decrease in response to hyperinsulinemia, ii) ghrelin abrogates the inhibitory effect of insulin on circulating RBP4 concentrations, and iii) ghrelin as well as GH acutely induces insulin resistance in skeletal muscle without significant changes in circulating RBP4 levels.

Retinol binding protein‐4 circulating levels were higher in nonalcoholic fatty liver disease vs. histologically normal liver from morbidly obese women

We aimed to analyze the retinol binding protein-4 (RBP4) messenger RNA (mRNA) expression profiles in adipose tissues and liver of morbidly obese (MO) women with or without nonalcoholic fatty liver disease (NAFLD), and to study the relationships with other pro- and anti-inflammatory adipokines in vivo and in vitro. We performed a cross-sectional analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and liver samples from four lean and 45 MO women with or without NAFLD by enzyme-linked immunosorbent assay and real-time reverse transcription-PCR. We also studied RBP4 expression in HepG2 hepatocytes under various inflammatory stimuli. Circulating RBP4 levels were higher in MO women, and specifically, in MO subjects with NAFLD compared with normal liver controls (lean and MO). RBP4 liver expression was higher in nonalcoholic steatohepatitis (NASH)-moderate/severe than in NASHmild. Overall RBP4 gene expression was higher in liver than in adipose tissues. Among them, the higher expression corresponded to SAT. VAT expression was lower in the MO cohort. In HepG2, RBP4 mRNA expression was reduced by tumor necrosis factor (TNF)-α and increased by adiponectin treatment. The results obtained in MO women with NAFLD, brings up the use of RBP4 and other adipokines as a panel of noninvasive molecular biomarkers when NAFLD is suspected. Further studies are needed with other obesity groups.

Adipokines as Possible New Predictors of Cardiovascular Diseases: A Case Control Study

Background and Aims. The secretion of several adipocytokines, such as adiponectin, retinol-binding protein 4 (RBP4), adipocyte fatty acid binding protein (aFABP), and visfatin, is altered in subjects with abdominal adiposity; these endocrine alterations could contribute to increased cardiovascular risk. The aim of the study was to assess the relationship among adiponectin, RBP4, aFABP, and visfatin, and incident cardiovascular disease. Methods and Results. A case-control study, nested within a prospective cohort, on 2945 subjects enrolled for a diabetes screening program was performed. We studied 18 patients with incident fatal or nonfatal IHD (Ischemic Heart Disease) or CVD (Cerebrovascular Disease), compared with 18 matched control subjects. Circulating adiponectin levels were significantly lower in cases of IHD with respect to controls. Circulating RBP4 levels were significantly increased in CVD and decreased in IHD with respect to controls. Circulating aFABP4 levels were significantly increased in CVD, while no difference was associated with IHD. Circulating visfatin levels were significantly lower in cases of both CVD and IHD with respect to controls, while no difference was associated with CVD. Conclusions. The present study confirms that low adiponectin is associated with increased incidents of IHD, but not CVD, and suggests, for the first time, a major effect of visfatin, aFABP, and RBP4 in the development of cardiovascular disease.