Plasma Retinol-binding Protein Concentrations Research Articles

Association between Circulating Retinol Binding Protein 4, Body Mass Index, and Biomarkers of Environmental Enteric Dysfunction among Slum-Dwelling Lean Adults in Bangladesh.

The relationship of retinol binding protein 4 (RBP4) with biomarkers of intestinal health and gut integrity in adults is unknown. We sought to determine the correlation between plasma RBP4 level and BMI and investigate the relationship of circulating RBP4 concentration with biomarkers of environmental enteric dysfunction among lean adults (body mass index [BMI] <25.0 kg/m2) in Bangladesh. Overall, 270 adults (135 undernourished with a BMI <18.5 kg/m2 and 135 healthy controls with a BMI between 18.5 and 24.9 kg/m2) aged 18 to 45 years were evaluated. Multivariable linear regression was performed to test the association between RBP4 and fecal biomarkers of impaired gut health. RBP4 concentration was positively correlated (rho = 0.27, P < 0.001) with BMI and was significantly higher in healthy controls than undernourished adults (P < 0.001), in male than female (P < 0.001), and also in employed (P < 0.001), smokers (P = 0.048) and participants with low Self-Reporting Questionnaire (SRQ)-20 scores (an instrument to screen mental health disorders) (P = 0.049). Statistically significant negative correlations were observed between RBP4 and fecal biomarkers of gut enteropathy including myeloperoxidase (rho = -0.23, P < 0.001), neopterin (rho = -0.30, P < 0.001), and alpha-1 anti-trypsin (rho = -0.21, P < 0.001). Multivariable linear regression analysis showed that increased RBP4 concentration was associated with a significant reduction in fecal neopterin (coefficient = -0.95; 95% confidence interval: -1.44 to -0.45]; P < 0.001) after adjustment for age, sex, nutritional status at enrollment, education, dietary diversity score, SRQ-20 score, improved sanitation, household animal exposure, and alpha-1-acid glycoprotein. The study findings revealed an inverse relationship of plasma RBP4 concentration with fecal biomarkers of altered gut health among slum-dwelling lean adults in Bangladesh.

Novel adipokine associated with OA: retinol binding protein 4 (RBP4) is produced by cartilage and is correlated with MMPs in osteoarthritis patients

ObjectiveRetinol binding protein 4 (RBP4) is a member of the lipocalin family and a vitamin A carrier in the blood. More recently, RBP4 has been described as an adipokine that is involved in insulin resistance and metabolic syndrome (MetS). As obesity, MetS and some adipokines contribute to the pathogenesis of osteoarthritis (OA), we investigated RBP4 in patients with OA.Materials and methodsCartilage, synovial fluid and blood samples were collected from 100 OA patients undergoing total knee replacement surgery. Primary chondrocytes and cartilage tissue were cultured to measure the RBP4 expression. The concentrations of RBP4, other adipokines (adipsin, adiponectin, leptin and resistin) and biomarkers of OA (COMP, MMP-1, MMP-3 and YKL-40) were measured by immunoassay, and gene expression was measured by next-generation RNA sequencing.ResultsThe OA cartilage samples released RBP4 into the culture medium, and the levels correlated positively with the expression of the adipokines adipsin, adiponectin, leptin and resistin. RBP4 was the most prominently expressed of these adipokines in the OA chondrocytes, and the expression of the RBP4 receptors STRA6 (stimulated by retinoic acid gene homologue 6) and TLR4 (Toll-like receptor 4) was also detected. Within the cartilage culture medium, RBP4 showed a positive correlation with MMP-1, MMP-3 and YKL-40. RBP4 was also present in the synovial fluid from the OA patients and correlated positively with the concentrations of RBP4 found in the plasma and the cartilage culture medium. Plasma RBP4 concentrations also showed a positive correlation with MMP-3 and adipsin.ConclusionsWe show here, for the first time, that RBP4 is produced within OA joints and that it is associated with increased levels of adipokines and MMPs. The results suggest a role for RBP4 in the pathogenesis of OA and as a possible target for the disease-modifying drugs for the treatment of OA.

Plasma retinol-binding protein 4 in the first and second trimester and risk of gestational diabetes mellitus in Chinese women: a nested case-control study

BackgroundTo assess the association between plasma retinol-binding protein 4 (RBP4) levels both in the first trimester and second trimester and risk of gestational diabetes mellitus (GDM).MethodsPlasma RBP4 levels and insulin were measured among 135 GDM cases and 135 controls nested within the Peking University Birth Cohort in Tongzhou. Multivariable linear regression analysis was conducted to assess the influence of RBP4 levels on insulin resistance. Conditional logistic regression models were used to compute the odds ratio (OR) and 95% confidence interval (CI) between RBP4 levels and risk of GDM.ResultsThe GDM cases had significantly higher levels of RBP4 in the first trimester than controls (medians: 18.0 μg/L vs 14.4 μg/L; P < 0.05). Plasma RBP4 concentrations in the first and second trimester were associated with fasting insulin, homeostasis model assessment for insulin resistance (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI) in the second trimester (all P < 0.001). With adjustment for diet, physical activity, and other risk factors for GDM, the risk of GDM increased with every 1-log μg/L increment of RBP4 levels, and the OR (95% CI) was 3.12 (1.08–9.04) for RBP4 in the first trimester and 3.38 (1.03–11.08) for RBP4 in the second trimester.ConclusionsPlasma RBP4 levels both in the first trimester and second trimester were dose-dependently associated with increased risk of GDM.

A Prospective Study of Maternal Plasma Concentrations of Retinol-Binding Protein 4 and Risk of Gestational Diabetes Mellitus

Background: The aim of this study was to investigate whether retinol-binding protein 4 (RBP4) concentrations, measured at the first prenatal visit, are associated with risk of gestational diabetes mellitus (GDM). Methods: From July 2015 to June 2016, consecutive women who admitted to the obstetrics center of our hospital were included. At the first prenatal visit (the median gestational age was 6 [interquartile range 4–10] weeks) in the hospital, involved subjects were tested for fasting plasma glucose (FPG) and RBP4 using venous plasma samples collected after at least 8 h of fasting in the morning. Data for FPG and RBP4 concentrations at the first prenatal visit and one-step GDM screening with 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation were collected and analyzed. Results: Blood at first prenatal visit was available for 827 women, among whom GDM developed in 101 (12.2%). In multivariate models comparing the second (Q2), third, and fourth quartiles against the first quartile of RBP4, concentrations of RBP4 in Q2, Q3, and Q4 were associated with GDM later developed, and increased risk of GDM by 54, 205, and 536%. There was a significant statistical difference in the area under the curve between the established risk factors alone and the addition of RBP4 concentrations (difference, 0.039 [95% CI 0.030–0.052]; p = 0.03). In the subgroup of women combined with obesity and FABP4 ≥median, the measured OR was 9.83 (95% CI [4.76–16.13]; p < 0.001) for GDM compared to those without obesity and FABP4 <median. Conclusions: There is evidence of a positive association of early pregnancy elevated RBP4 concentration with increased GDM risk, particularly among women with advanced age and obesity.

Elevated RBP4 plasma levels were associated with diabetic retinopathy in type 2 diabetes.

The retinol-binding protein 4 (RBP4) has been postulated to play a role in glucose homeostasis, insulin resistance, and diabetes mellitus in human and animal studies. The aim of the present study was to evaluate the role of RBP4 in Chinese patients with type 2 diabetes mellitus with and without diabetic retinopathy (DR). Plasma RBP4 concentrations were tested in 287 patients with type 2 diabetes. At baseline, demographic and clinical information including presence of DR and vision-threatening DR (VTDR) was collected. The relationship between RBP4 and DR (VTDR) was investigated using logistic regression. Patients with DR or VTDR had significantly higher plasma levels of RBP4 on admission (P<0.0001). Receiver operating characteristics (ROCs) to predict DR and VDTR demonstrated areas under the curve for RBP4 of 0.79 (95% confidence interval (CI): 0.73–0.85) and 0.90 (95% CI: 0.85–0.94), respectively, which were superior to other factors. For each 1 μg/ml increase in plasma level of RBP4, the unadjusted and adjusted risk of DR would be increased by 8% (with the odds ratio (OR) of 1.08 (95% CI: 1.05–1.13), P<0.001) and 5% (1.05 (1.02–1.11), P=0.001), respectively. It was 12% (with the OR of 1.12 (95% CI: 1.07–1.18), P<0.001) and 9% (1.09 (1.05–1.15), P<0.001) for VTDR. The present study shows that elevated plasma levels of RBP4 were associated with DR and VDTR in Chinese patients with type 2 diabetes, suggesting a possible role of RBP4 in the pathogenesis of DR complications. Lowering RBP4 could be a new strategy for treating type 2 diabetes with DR.

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 different intensities exercise combined with resveratrol on RBP4 in aged obese rats

To investigate the effects of different intensity exercise combined with resveratrol on retinol binding protein 4(RBP4) mRNA and protein expression in visceral adipose tissue and plasma RBP4 concentration of aged obese rats. Eighty male SD rats aged 3 weeks were randomly divided into the control group and the experimental group. Rats of the control group(C) were fed with ordinary feed of 6% fat (n=12). The experimental group consisted of 68 rats, which were fed with 36%~40% high fat feed in three stages. The rat model of elderly obesity was established successfully. Twenty-four obese rats were selected and randomly divided into 4 groups, including obese group (CO), resveratrol obese group (RO), low intensity exercise combined with resveratrol group (LRO) and moderate intensity exercise combined with resveratrol group (MRO). There were 6 rats in each group. The exercise intensities of the LRO group and MRO group were (12 m/min×15 min) and (15 m/min×15 min). Every day was exercised for 60 minutes. The rats in RO, LRO or MRO were treated with resveratrol at the dose of 52.5 mg/kg·d, while the rats in the control group were fed with the same amount of purified water, continued intervention for 8 weeks. After 8 weeks, samples of blood, adipose tissue of around the kidney, testicle, vessel and visceral were collected. Blood glucose and plasma RBP4 concentration were measured. Insulin sensitivity(ISI) was calculated. The expressions of RBP4 mRNA and protein were also determined. Compared with normal (C) group, the expressions of RBP4 mRNA and protein and plasma concentration and plasma glucose of the model (CO) group were increased obviously (P<0.05, P<0.01). ISI was decreased obviously (P<0.05). Compared with model (CO) group, the expressions of RBP4 mRNA and protein and plasma concentration and plasma glucose of the RO and LRO and MRO groups were decreased significantly(P<0.05, P<0.01), while ISI was increased markedly (P<0.05). Compared with the RO and LRO groups, the expressions of RBP4 mRNA and protein and plasma concentration and plasma glucose of the MRO group were decreased, while ISI was increased, but there was no significant difference. Different intensities exercise combined with resveratrol could reduce the RBP4 mRNA and protein expression in visceral adipose tissue and plasma RBP4 concentrations of aged obese rats, but less affected by exercise intensity.

The Effect of Different High Fat Diets on Plasma Concentration and Hepatic Expression of Retinol‐Binding Protein 4 in Rats

Retinol‐binding protein 4 (RBP4) has been associated with insulin resistance and hepatic steatosis. Production of hepatic insulin resistance by high‐fat diets depends on their fatty acid composition. Here, the effect of three high‐fat diets on plasma concentration and hepatic expression of RBP4 (Rbp4) was compared with respect to insulin resistance, dyslipidemia, and hepatic steatosis.Weight‐matched groups (N=10/group) of male Sprague‐Dawley rats received one of four diets for eight weeks: low‐fat control (LF, 15% kcal as fat), or a high‐fat (HF, 55% kcal as fat) safflower oil (polyunsaturated), olive oil (cis‐monounsaturated, MUFA) or a trans‐fat (trans‐MUFA) diet. Blood samples were collected as a time course study at wks 3, 6, and 9 (N=16), and after an eight‐week feeding in the fasted or refed (fat‐free, high carbohydrate meal) state (N=40). Liver samples were collected at wk 9 in the fasted or refed state to compare plasma concentration and hepatic expression of RBP4 (Rbp4) and its response to insulin. Plasma RBP4 concentrations were measured by enzyme‐linked immunosorbent assay (ELISA). Hepatic expression of Rbp4 and other genes (e.g. Srebf, Fasn) was measured by real‐time PCR.Body weights and percent body fat of all HF groups were similar at wk 9. Plasma RBP4 concentrations were higher in the trans‐fat vs. the LF group at wk 3, 6, and 9 (p&lt; 0.05). The olive oil and the trans‐fat group had elevated plasma RBP4 at wk 9 vs. the LF group (p&lt;0.05). Liver expression of Rbp4 under fasted or re‐fed conditions did not differ among the groups, a finding consistent with a non‐hepatic (e.g. adipose tissue) source of RBP4. The olive oil group had higher fasting plasma insulin levels (p&lt;0.05), higher HOMA‐IR values (p&lt;0.005), higher liver lipid concentration (p &lt; 0.05) vs. other groups. Expression of hepatic genes in the lipogenic pathway was positively correlated with plasma triglyceride levels in both the olive oil and trans‐fat groups (p&lt; 0.05), and the olive oil group had greater stimulation of lipogenic gene expression by refeeding than did other groups (p&lt;0.05). The HF safflower group did not show differences from the LF group at wk 9.The HF olive oil (cis‐MUFA) diet was associated with elevated plasma RBP4, hyperinsulinemia, hepatic steatosis and insulin resistance, as well as an enhanced hepatic expression of lipogenic genes. The HF trans‐fat (trans‐MUFA) diet was also associated with elevated plasma RBP4 and increased lipogenic gene expression, and both MUFA groups showed this expression to be correlated with plasma triglyceride levels. These findings show that HF diet‐induced increases in RBP4 are dependent on the type of fat and suggest that non‐hepatic RBP4 may promote hepatic expression of lipogenic genes.

Increased plasma RBP4 concentration in older hypertensives is related to the decreased kidney function and the number of antihypertensive drugs—results from the PolSenior substudy

Increased plasma retinol-binding protein 4 (RBP4), a novel adipokine, has been associated in previous studies with obesity, type 2 diabetes, dyslipidemia, hypertension (HT), atherosclerosis, and coronary artery disease. This study aimed to analyze the relationship between HT occurrence and its treatment, and plasma RBP4 concentrations in the older polish population. The study sample consisted of 1728 (890 men and 838 women) PolSenior study participants aged 65 years and older with available plasma samples and NT-proBNP values below 2000 pg/mL. The analysis included body mass index, waist circumference, blood pressure, antihypertensive medication, estimated glomerular filtration rate, serum glucose and insulin (and the homeostatic model assessment of insulin resistance), and plasma RBP4 levels. RBP4 plasma concentrations were higher in hypertensive (N = 645) than normotensive (N = 236) men (43.4 [30.4–64.8] vs. 38.1 [27.1–54.4] ng/mL, respectively; P < .01) but not in women (44.6 [29.6–63.5] vs. 40.7 [29.1–58.1] ng/mL, respectively; P = .21). In the subanalysis, higher plasma RBP4 levels were observed in women with treated than untreated HT and in subjects taking four of more antihypertensive drugs. The linear regression shown that estimated glomerular filtration rate (β = −0.015), thiazide diuretics (β = 0.041), and α-blockers (β = 0.049) were explaining log10RBP4 plasma levels variability in the study group. Older male Caucasians with HT are characterized by elevated plasma RBP4 levels. This increase is proportional to the number of antihypertensive drugs and decreased glomerular filtration rate. Among the antihypertensive drugs, only thiazide diuretics and α-blockers had a significant influence on RBP4 levels.

Involvement of RBP4 in hyperinsulinism-induced vascular smooth muscle cell proliferation.

Retinol-binding protein 4 (RBP4) is a newly discovered adipocytokine related to insulin resistance (IR). Hyperinsulinemia and IR are the major risk factors for cardiovascular diseases (CVD). The role of RBP4 in CVD has not yet been determined. The present study was designed to analyze the correlation of RBP4 and CVD risk factors and to evaluate the role of RBP4 in proliferation of vascular smooth muscle cells during hyperinsulinemia and the underlying mechanisms. Plasma RBP4 concentration, IR-related indexes, and cardiovascular risk factors were measured from blood samples of hyperinsulinemic rats (HIns) and control SD rats (Cons). The vascular morphology and the expression of ERK1/2, p-ERK1/2 in arterial tissues of rats were assessed. Different concentrations of RBP4 (1, 4 μg/ml) were used as intervention factor during insulin-induced aortic smooth muscle cells (RASMCs) proliferation. The expression of cell growth signaling pathways was assessed to identify the active pathway during this proliferation. Specifically, ERK1/2 inhibitor PD98059 and JAK2 inhibitor AG490 were used to detect it. RBP4 expression was higher in HIns compared with Cons (p < 0.01). Plasma RBP4 concentrations were positively correlated with TG (r = 0.490), hsCRP (r = 0.565), media thickness (r = 0.890), and p-ERK1/2 protein (r = 0.746) (p < 0.05 each). In cultured RASMCs, RBP4 enhanced insulin-induced proliferation of cells and expression of p-ERK1/2 and p-JAK2. Blockade of ERK1/2 signaling pathway inhibited RBP4-induced proliferation of RASMCs, while suppressing JAK2 remains unchanged. These results suggest that plasma RBP4 concentrations were associated with CVD. In addition, RBP4 increases the proliferation of VSMCs induced by hyperinsulinism via activation of MAPK signaling pathway.

Elevated Plasma Retinol-Binding Protein 4 Is Associated with Increased Risk of Type 2 Diabetes in Middle-Aged and Elderly Chinese Adults1–3

The association between circulating retinol-binding protein 4 (RBP4) and risk of type 2 diabetes has been inconsistent in cross-sectional studies, but prospective evidence is limited. We aimed to investigate whether plasma RBP4 is associated with future development of type 2 diabetes and whether the association could be explained by iron or other risk factors. A total of 2091 Chinese adults aged 50–70 y were followed up for 6 y. Baseline dietary intakes and fasting plasma RBP4, ferritin, adiponectin, C-reactive protein (CRP), γ-glutamyltransferase, creatinine, and erythrocyte fatty acids were determined. Self-reported doctor-diagnosed diabetes, or usage of antidiabetic agents, or fasting plasma glucose concentration at the follow-up visit ≥7.0 mmol/L was defined as an incident diabetes case. Plasma RBP4 concentration was significantly associated with dietary heme iron intake, plasma ferritin concentration, and other established risk factors. After multivariate adjustment for demographic and lifestyle variables, relative risk (RR) for type 2 diabetes when the extreme quartiles of RBP4 were compared was 1.75 (95% CI: 1.30, 2.37; P-trend < 0.001). This association remained significant when the extreme quartiles were compared (RR = 1.48; 95% CI: 1.06, 2.05; P-trend = 0.036) after further controlling for ferritin and dietary factors, as well as other risk factors, including body mass index, adiponectin, CRP, lipids, liver and kidney function, insulin resistance, and hypertension. A threshold effect of RBP4 concentrations on incident diabetes was suggested by restricted quadratic spline analysis (P = 0.026 for nonlinearity). Our study indicates that plasma RBP4 is independently associated with the 6-y risk of developing type 2 diabetes.

Breast Milk Retinol and Plasma Retinol-Binding Protein Concentrations Provide Similar Estimates of Vitamin A Deficiency Prevalence and Identify Similar Risk Groups among Women in Cameroon but Breast Milk Retinol Underestimates the Prevalence of Deficiency among Young Children1–3

Breast milk vitamin A (BMVA) has been proposed as an indicator of population vitamin A status but has rarely been applied in large-scale surveys or compared with conventional vitamin A biomarkers. We assessed the prevalence of, and risk factors for, low BMVA and its relation to vitamin A intake, plasma retinol-binding protein (pRBP), and markers of inflammation in a national survey in Cameroon. We randomly selected 30 clusters in each of 3 strata (South, North, and Cities). Casual milk samples were collected from approximately 5 women per cluster (n = 440). pRBP, plasma C-reactive protein (pCRP), plasma α1-acid glycoprotein (pAGP), and 24-h vitamin A intake were assessed in 10 women aged 15–49 y and 10 children aged 12–59 mo per cluster, including a subset of lactating women (n = 253). Low BMVA was infrequent: 7.2% (95% CI: 4.7, 9.8) of values were <1.05 μmol/L, and 9.3% (95% CI: 5.8, 12.7) were <8 μg/g fat, consistent with the low prevalence of pRBP <0.78 μmol/L among women (< 5%) but lower than the prevalence of pRBP <0.83 μmol/L among children (35%). Risk factors for both low BMVA and pRBP included living in the North and low maternal education. BMVA was positively associated with inflammation-adjusted pRBP among women in the lowest vitamin A intake tertile [<115 μg retinol activity equivalents (RAEs)/d, P < 0.01] but not in the highest tertile (>644 μg RAEs/d, P > 0.4). Controlling for milk fat, BMVA was negatively associated with pCRP (P < 0.02) but not pAGP (P > 0.5). BMVA and pRBP provide similar estimates of vitamin A deficiency prevalence and identify the same risk groups among women in Cameroon, but BMVA underestimates the prevalence of vitamin A deficiency among young children.

The Association of Retinol-Binding Protein 4 With Metabolic Syndrome and Obesity in Adolescents

Retinol-binding protein 4 (RBP4) has a role in the development of insulin resistance (IR), type 2 diabetes, obesity, and metabolic syndrome among adults. However, data among adolescents are limited, and the effects of gender and sex hormones on RBP4 are not well defined. A total of 1082 adolescents were enrolled and categorized based on their body mass index. Blood samples were collected, and biochemical characteristics, sex hormones, RBP4 concentrations, and IR were determined. Testosterone and estradiol were not directly correlated with RBP4 concentrations in both genders. Multivariate regression analysis revealed that fasting plasma glucose (FPG), triglyceride (TG), and testosterone levels were independently associated with RBP4 concentrations in boys; also, there was a trend of increasing RBP4 levels with the severity of obesity. Plasma RBP4 concentrations correlated with obesity and cardiovascular risk factors, predominantly evident in boys. Testosterone, FPG, and TG levels were independent predictors of RBP4 concentrations.

Toll-like receptors 1–9 are elevated in livers with fructose-induced hepatic steatosis

Studies in animals and human subjects indicate that gut-derived bacterial endotoxins may play a critical role in the development of non-alcoholic fatty liver disease (NAFLD). In the present study, we investigated if the liver is also sensitised by other microbial components during the onset of fructose-induced steatosis in a mouse model. C57BL/6 mice were either fed with 30 % fructose solution or tap water (control) with or without antibiotics for 8 weeks. Expression of toll-like receptors (TLR)1-9, TNF-α, inducible NO synthase (iNOS), myeloid differentiation factor 88 (MyD88) and number of F4/80 positive cells in the liver were assessed. Occludin protein, DNA of microbiota in the small and large intestine and retinol binding protein 4 (RBP4) in plasma were analysed using Western blot, DNA fingerprinting and ELISA, respectively. F4/80 positive cells were determined by immunohistochemistry. The accumulation of TAG found in the livers of fructose-fed mice was associated with a significant induction of TLR 1-4 and 6-8. Plasma RBP4 concentration and hepatic mRNA expression levels of TNF-α, iNOS, MyD88 and number of F4/80 positive cells of fructose-fed animals were significantly higher than those of controls; however, these effects of fructose were attenuated in antibiotic-treated mice. Whereas protein concentration of occludin was lower in the duodenum of fructose-treated mice, no systematic alterations of microbiota were found in this part of the intestine. Taken together, these data support the hypothesis that (1) an increased intestinal translocation of microbial components and (2) an increased number of F4/80 positive cells and induction of several TLR and dependent pathways (e.g. MyD88 and iNOS) may be involved in the onset of fructose-induced NAFLD.

The Effect of Rosiglitazone on Retinol Binding Protein 4 in Subjects of Impaired Glucose Tolerance

Abstract: Retinol-binding protein-4 (RBP4) is a novel adipokine, which is reported to be associated with obesity and insulin resistance (IR). We studied the effect of rosiglitazone (ROS), an insulin sensitizer, on the RBP4 plasma concentrations in subjects with impaired glucose tolerance (IGT). A single-blind, placebo-controlled comparison trial was conducted. A total of 26 IGT patients (mean age of 54 years) were enrolled; 14 received ROS (4 mg daily) and 12 received placebo. An enzyme immunoassay (EIA) was used to measure plasma RBP4 concentrations before and after therapy in both treatment groups. Plasma RBP4 concentrations were not associated with IR and cardiovascular risk factors with the exception of serum creatine levels. ROS therapy decreased RBP4 levels independent of IR, but associated with the changes in aspartate aminotransferase and triglyceride levels as well as basal serum RBB4 concentrations. In brief, plasma RBP4 concentrations in IGT subjects did not correlate with most cardiovascular risk factors and IR. However, treating IGT subjects with ROS resulted in decreased RBP4 levels independent of IR.

Nonalcoholic Fatty Liver Disease as the Transducer of Hepatic Oversecretion of Very-Low-Density Lipoprotein–Apolipoprotein B-100 in Obesity

To examine the association between liver fat content and very low-density lipoprotein (VLDL)-apolipoprotein (apo) B-100 kinetics and the corresponding responses to weight loss in obese subjects. VLDL-apoB-100 kinetics were assessed using stable isotope tracers, and the fat content of the liver and abdomen was determined by magnetic resonance techniques in 25 obese subjects. In univariate analysis, liver fat content was significantly (P<0.05 in all) associated with body mass index (r=0.65), visceral fat area (r=0.45), triglycerides (r=0.40), homeostasis model assessment score (r=0.40), VLDL-apoB-100 concentrations (r=0.44), and secretion rate (r=0.45). However, liver fat content was not associated with plasma concentrations of retinol-binding protein 4, fetuin A, adiponectin, interleukin-6, and tumor necrosis factor-alpha. Of these 25 subjects, 9 diagnosed as having nonalcoholic fatty liver disease (which is highly prevalent in obese individuals and strongly associated with dyslipidemia) underwent a weight loss program. The low-fat diet achieved significant reduction in body weight, body mass index, liver fat, visceral and subcutaneous fat areas, homeostasis model assessment score, triglycerides, VLDL-apoB-100 concentrations, and VLDL-apoB-100 secretion rate. The percentage reduction of liver fat with weight loss was significantly associated with the corresponding decreases in VLDL-apoB-100 secretion (r=0.67) and visceral fat (r=0.84). In patients with obesity, hepatic steatosis increases VLDL-apoB-100 secretion. Weight loss can help reduce this abnormality.

Association Between Retinol-Binding Protein 4 Concentrations and Gestational Diabetes Mellitus and Risk of Developing Metabolic Syndrome After Pregnancy

The aim of this study was to examine the association between plasma retinol-binding protein 4 (RBP4) and gestational diabetes mellitus (GDM) and the risk of developing metabolic syndrome after pregnancy. In a case-control study, 192 pregnant women (92 with GDM) were recruited. Gestational diabetes mellitus was diagnosed based on O'Sullivan and Mahan criteria. In all pregnancies, plasma RBP4 concentrations were measured. Retinol-binding protein 4 concentrations in GDM patients were significantly higher than the normal women. Retinol-binding protein 4 level equal to or more than 42 microg/mL could help predict the risk of developing GDM (sensitivity = 75.8%, specificity = 65.3%, P = .001). Concerning metabolic syndrome after pregnancy, in all participants, the prevalence of metabolic syndrome base on World Health Organization (WHO) criteria was 24%. After pregnancy, 32.6% of women with GDM had metabolic syndrome compared with 10.5% of those with healthy pregnancy (P = .001). Age more than 25 years, body mass index (BMI) more than 27 kg/cm(2), and RBP4 concentrations were independent risk factors for GDM. Measurement of RBP4 together with the assessment of other risk factors could help identify women at risk of developing GDM.

Retinol-binding protein 4: a novel adipokine implicated in the genesis of LGA in the absence of gestational diabetes mellitus

Adipokines (cytokines produced by adipose tissue) play a major role in the control of body weight and energy distribution. Retinol-binding protein 4 (RBP4), only recently recognized as an adipokine, has been proposed to modulate systemic insulin sensitivity. The goal of this study was to determine whether there is an association between maternal plasma RBP4 concentration and the birth of a large-for-gestational-age (LGA) newborn in women with and without gestational diabetes mellitus (GDM). This cross-sectional study included pregnant women at term in the following groups: 1) normal pregnancy with an appropriate-for-gestational-age (AGA) neonate (n=64); 2) normal pregnancy with an LGA neonate (n=44); 3) GDM with an AGA neonate (n=55); and 4) GDM with an LGA neonate (n=42). Maternal plasma RBP4 concentration was determined by ELISA. Parametric and non-parametric statistics were used for analyses. 1) Patients with GDM, either with AGA or LGA neonates, had a higher median plasma concentration of RBP4 than normal pregnant women who delivered an AGA neonate (P=0.01 and P=0.008, respectively); 2) mothers without GDM but with LGA neonates had a higher median plasma concentration of RBP4 than those with normal pregnancy and AGA newborns (P=0.001); 3) these findings remained significant after adjusting for maternal age, body mass index and gestational age at blood sampling. GDM is characterized by alterations in maternal circulating RBP4 concentrations akin to those of Type 2 diabetes mellitus. RBP4 concentrations in maternal plasma may play a role in accelerated fetal growth in the absence of overt carbohydrate intolerance.

Retinol binding protein 4--a novel association with early-onset preeclampsia.

Dysregulation of maternal circulating adipokines has been implicated in several "great obstetrical syndromes" including preeclampsia (PE), small-for-gestational age (SGA) neonate and fetal death (FD). It has been suggested that adipokines provide a molecular link between metabolic derangements and inflammatory response in complicated pregnancies. Retinol binding protein 4 (RBP4), a novel adipokine, plays a role in obesity-related disorders, as well as in the regulation of the immune response. The aim of this study was to determine whether there are changes in maternal plasma concentrations of RBP4 in patients with PE and in those with an SGA neonate or FD. This cross-sectional study included patients in the following groups: 1) normal pregnancy (n=134); 2) PE (n=104); 3) SGA neonate (n=28); and 4) FD (n=37). Maternal plasma RBP4 concentrations were determined by ELISA. Non-parametric statistics were used for analysis. 1) The median maternal plasma RBP4 concentration was higher among patients with PE than in those with a normal pregnancy (P=0.03); 2) The median maternal plasma RBP4 concentrations of patients with preterm PE (<37 weeks) was higher than that of those with term PE (P=0.017) and than that of those with a normal pregnancy (P=0.002); 3) The median maternal plasma RBP4 concentration did not differ significantly between patients with a normal pregnancy and those with an SGA neonate or with an FD; 4) Among normal pregnant women, the maternal plasma RBP4 concentrations did not correlate with pre-pregnancy body mass index, gestational age at blood sampling and neonatal birthweight. 1) Preeclampsia, but not pregnancy with an SGA neonate or an FD, is associated with a higher median maternal plasma concentration of RBP4 than normal pregnancy; 2) Preterm PE, and specifically early-onset PE, is associated with higher median RBP4 concentrations in maternal plasma compared to term PE. These findings suggest a role for RBP4 in the pathogenesis of preterm PE, but not in SGA and FD.

Discriminated benefits of a Mediterranean dietary pattern within a hypocaloric diet program on plasma RBP4 concentrations and other inflammatory markers in obese subjects

Personalized nutritional strategies to treat obesity may specifically influence inflammatory markers, in addition to reduce body weight. In the present study, we evaluated the effect of a hypocaloric diet based on a Mediterranean dietary pattern (MDP) on nutritional status as well as on plasma concentrations of retinol binding protein-4 (RBP4) and other proinflammatory markers. Fourty-one subjects (24F/17M; age: 37 ± 7 years; BMI: 32.2 ± 3.9 kg/m²) were assigned to follow a MDP within a caloric-restricted diet over an 8-week period. Anthropometrical, clinical, and biochemical variables were measured at baseline and endpoint after the nutritional program. Dietary intervention resulted in a mean weight loss of -4.4 ± 2.5 kg (P < 0.001) and marked reductions (P < 0.05) in plasma concentrations of RBP4, leptin, C-reactive protein, complement C3, and tumor necrosis factor-alpha (TNFα). Individuals with a higher adherence to the MDP during the nutritional intervention presented differentially higher reductions (P < 0.05) in plasma RBP4, IL6, and TNFα. In addition, the increase in the Mediterranean diet score from baseline was a significant and independent predictor factor for the decrease in plasma RBP4 concentration (P < 0.05). In conclusion, our findings suggest that following a hypocaloric diet accompanying a high adherence to a MDP resulted in specific reductions on proinflammatory markers, in addition to a significant improvement in some metabolic syndrome features induced by weight loss, which could be a good combined strategy to treat obesity as well as related metabolic and inflammatory disorders.