Adipose Signals Regulating Distal Organ Health and Disease.

Excessive adiposity in obesity is a significant risk factor for development of type 2 diabetes (T2D), nonalcoholic fatty liver disease, and other cardiometabolic diseases. An unhealthy expansion of adipose tissue (AT) results in reduced adipogenesis, increased adipocyte hypertrophy, adipocyte hypoxia, chronic low-grade inflammation, increased macrophage infiltration, and insulin resistance. This ultimately culminates in AT dysfunction characterized by decreased secretion of antidiabetic adipokines such as adiponectin and adipsin and increased secretion of proinflammatory prodiabetic adipokines including RBP4 and resistin. This imbalance in adipokine secretion alters the physiological state of AT communication with target organs including pancreatic ß-cells, heart, and liver. In the pancreatic ß-cells, adipokines are known to have a direct effect on insulin secretion, gene expression, cell death, and/or dedifferentiation. For instance, impaired secretion of adipsin, which promotes insulin secretion and ß-cell identity, results in ß-cell failure and T2D, thus presenting a potential druggable target to improve and/or preserve ß-cell function. The cardiac tissue is affected by both the classic white AT-secreted adipokines and the newly recognized brown AT (BAT)-secreted BATokines or lipokines that alter lipid deposition and ventricular function. In the liver, adipokines affect hepatic gluconeogenesis, lipid accumulation, and insulin sensitivity, underscoring the importance of adipose-liver communication in the pathogenesis of nonalcoholic fatty liver disease. In this perspective, we outline what is currently known about the effects of individual adipokines on pancreatic ß-cells, liver, and the heart.

Succinate-induced macrophage polarization and RBP4 secretion promote vascular sprouting in ocular neovascularization.

Pathological neovascularization is a pivotal biological process in wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR), in which macrophages (Mφs) play a key role. Tip cell specialization is critical in angiogenesis; however, its interconnection with the surrounding immune environment remains unclear. Succinate is an intermediate in the tricarboxylic acid (TCA) cycle and was significantly elevated in patients with wet AMD by metabolomics. Advanced experiments revealed that SUCNR1 expression in Mφ and M2 polarization was detected in abnormal vessels of choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) models. Succinate-induced M2 polarization via SUCNR1, which facilitated vascular endothelial cell (EC) migration, invasion, and tubulation, thus promoting angiogenesis in pathological neovascularization. Furthermore, evidence indicated that succinate triggered the release of RBP4 from Mφs into the surroundings to regulate endothelial sprouting and pathological angiogenesis via VEGFR2, a marker of tip cell formation. In conclusion, our results suggest that succinate represents a novel class of vasculature-inducing factors that modulate Mφ polarization and the RBP4/VEGFR2 pathway to induce pathological angiogenic signaling through tip cell specialization.

Effect of non-surgical periodontal treatment on cytokines/adipocytokines levels among periodontitis patients with or without obesity: a systematic review and meta-analysis.

BACKGROUND: The objective of this systematic review and meta-analysis was to evaluate the effects of non-surgical periodontal therapy (NSPT) on inflammatory-related cytokines/adipocytokines in periodontitis patients with or without obesity. METHODS: We followed the preferred reporting items for systematic reviews and meta-analyses statement and registered the study (CRD42022375331) in the Prospective International Register of Systematic Reviews. We screened randomized-controlled trials and controlled clinical trials from six databases up to December 2022. Quality assessment was performed with RoB-2 and ROBINS-I tools for randomized trials and non-randomized trials, respectively. Meta-analysis was carried out using a random-effect model. RESULTS: We included seventeen references in the systematic analysis, and sixteen in the meta-analysis. Baseline results of pro-inflammatory biomarkers, including serum interleukin (IL)-6, serum and gingival crevicular fluid (GCF), tumor necrosis factor (TNF)-a, serum C-reactive protein (CRP)/hs-CRP, and serum and GCF resistin, were higher in obesity subjects than in normal weight subjects. The effect of NSPT with respect to levels of cytokines/adipocytokines, including IL-6, TNF-a, CRP/hs-CRP, resistin, adiponectin, leptin and retinol binding protein 4 (RBP4), were then analyzed in the systematic and meta-analysis. After three months of NSPT, serum (MD = -0.54, CI = -0.62 - -0.46), and GCF (MD = -2.70, CI = -4.77 - -0.63) levels of IL-6, along with the serum RBP4 (MD = -0.39, CI = -0.68-0.10) decreased in periodontitis individuals with obesity. NSPT also improved GCF adiponectin levels after three months (MD = 2.37, CI = 0.29 - 4.45) in periodontitis individuals without obesity. CONCLUSIONS: Obese status altered the baseline levels of cytokines/adipocytokines (serum IL-6, serum and GCF TNF-a, serum CRP/hs-CRP, and serum and GCF resistin). Then NSPT can shift the levels of specific pro-inflammatory mediators and anti-inflammatory mediators in biological fluids, both in obesity and non-obesity individuals. NSPT can reduce serum and GCF IL-6 levels together with serum RBP4 level in individuals with obesity after 3 months, besides, there is no sufficient evidence to prove that obese patients have a statistically significant decrease in the levels of other cytokines compared to patients with normal weight. NSPT can also increase GCF adiponectin level in normal weight individuals after 3 months. Our findings imply the potential ideal follow-up intervals and sensitive biomarkers for clinical bioanalysis in personalized decision-making of effect of NSPT due to patients' BMI value.

Clinical, genetic and biochemical signatures of RBP4-related ocular malformations.

BACKGROUND: The retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with monoallelic and biallelic pathogenic variants in retinol-binding protein 4 (RBP4), encoding a serum retinol-specific transporter, display variable ocular phenotypes. Although few families have been reported worldwide, recessive inherited variants appear to be associated with retinal degeneration, while individuals with dominantly inherited variants manifest ocular development anomalies, mainly microphthalmia, anophthalmia and coloboma (MAC). METHODS: We report here seven new families (13 patients) with isolated and syndromic MAC harbouring heterozygous RBP4 variants, of whom we performed biochemical analyses. RESULTS: For the first time, malformations that overlap the clinical spectrum of vitamin A deficiency are reported, providing a link with other RA disorders. Our data support two distinct phenotypes, depending on the nature and mode of inheritance of the variants: dominantly inherited, almost exclusively missense, associated with ocular malformations, in contrast to recessive, mainly truncating, associated with retinal degeneration. Moreover, we also confirm the skewed inheritance and impact of maternal RBP4 genotypes on phenotypical expression in dominant forms, suggesting that maternal RBP4 genetic status and content of diet during pregnancy may modify MAC occurrence and severity. Furthermore, we demonstrate that retinol-binding protein blood dosage in patients could provide a biological signature crucial for classifying RBP4 variants. Finally, we propose a novel hypothesis to explain the mechanisms underlying the observed genotype-phenotype correlations in RBP4 mutational spectrum. CONCLUSION: Dominant missense variants in RBP4 are associated with MAC of incomplete penetrance with maternal inheritance through a likely dominant-negative mechanism.

Factors and Molecular Mechanisms of Vitamin A and Childhood Obesity Relationship: A Review.

Childhood obesity has become a public health concern. As the importance of vitamin A (VA) in the body has become increasingly acknowledged, there is limited clinical trial evidence to substantiate the association between VA and childhood obesity. Vitamin A deficiency (VAD) increases the risk of childhood obesity, a finding consistently reported in pregnant women. VA could regulate the adipogenic process, inflammation, oxidative stress and metabolism-related gene expression in mature adipocytes. VAD disrupts the balance of obesity-related metabolism, thus affecting lipid metabolism and insulin regulation. Conversely, VA supplementation has a major impact on efficacy in obesity, and obese individuals typically have a lower VA status than normal-weight individuals. Several studies have attempted to identify the genetic and molecular mechanisms underlying the association between VA and obesity. In this review, we summarize and discuss recent new developments focusing on retinol, retinoic acid, and RBP4 and elucidate and provide an overview of the complex interrelationships between these critical components of VA and childhood obesity. However, the causal relationship between VA status and childhood obesity remains unclear. It is also unknown whether VA supplementation improves the overall obesogenic metabolic profile.

RBP4-based Multimarker Score: A Prognostic Tool for Adverse Cardiovascular Events in Acute Coronary Syndrome Patients.

CONTEXT: Retinol binding protein 4 (RBP4) has been implicated in the progression of cardiovascular diseases. However, its association with major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS) remains obscure. OBJECTIVE: Here, we examined the prognostic value of baseline RBP4 and its derived multimarker score for MACEs in ACS patients. METHODS: A total of 826 patients with ACS were consecutively recruited from the department of cardiology and prospectively followed up for a median of 1.95 years (interquartile range, 1.02-3.25 years). Plasma RBP4 was measured using enzyme-linked immunosorbent assay. Adjusted associations between RBP4 and its derived multimarker score (1 point was assigned when RBP4 ≥ 38.18µg/mL, left ventricular ejection fraction [LVEF] ≤ 55%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥ 450 ng/L, estimated glomerular filtration rate [eGFR] ≤ 90 mL/min/1.73 m2, and age ≥60) with MACEs were analyzed. RESULTS: In total, 269 ACS patients (32.57%) experienced MACEs. When patients were grouped by multimarker score (0-1, n = 315; 2-3, n = 406; 4-5, n = 105), there was a significant graded association between RBP4-based multimarker score and risk of MACEs (intermediate score (2-3): HRadj: 1.80; 95% CI, 1.34-2.41; high score (4-5): HRadj: 3.26; 95% CI, 2.21-4.81) and its components (P < .05 for each). Moreover, the prognostic and discriminative value of the RBP4-derived multimarker score remained robust in ACS patients with various high-risk anatomical or clinical characteristics. CONCLUSION: The RBP4-derived 5-item score serves as a useful risk stratification and decision support for secondary prevention in patients with ACS.

A computational approach for the identification of key genes and biological pathways of chronic lung diseases: a systems biology approach.

BACKGROUND: Chronic lung diseases are characterized by impaired lung function. Given that many diseases have shared clinical symptoms and pathogenesis, identifying shared pathogenesis can help the design of preventive and therapeutic strategies. This study aimed to evaluate the proteins and pathways of chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and mustard lung disease (MLD). METHODS AND RESULTS: After collecting the data and determining the gene list of each disease, gene expression changes were examined in comparison to healthy individuals. Protein-protein interaction (PPI) and pathway enrichment analysis were used to evaluate genes and shared pathways of the four diseases. There were 22 shared genes, including ACTB, AHSG, ALB, APO, A1, APO C3, FTH1, GAPDH, GC, GSTP1, HP, HSPB1, IGKC, KRT10, KRT9, LCN1, PSMA2, RBP4, 100A8, S100A9, TF, and UBE2N. The major biological pathways in which these genes are involved are inflammatory pathways. Some of these genes activate different pathways in each disease, leading to the induction or inhibition of inflammation. CONCLUSION: Identification of the genes and shared pathways of diseases can contribute to identifying pathogenesis pathways and designing preventive and therapeutic strategies.

The inverse association between fasting blood glucose and the occurrence of gallbladder cancer in type 2 diabetes mellitus patients: a case-control study.

OBJECTIVE: This study aimed to explore the correlation between diabetes mellitus (DM) and gallbladder cancer (GBC) in an epidemiological setting. METHODS: The study summarized the clinical and laboratory data of 2210 GBC Chinese patients in the authors' hospital. A total of 17 influencing factors for GBC, including gender, body mass index (BMI), fasting blood glucose (FBG), fasting insulin (FINS), the homeostasis model assessment of insulin resistance (HOMA-IR), retinol-binding protein 4 (RBP4), and lipid indexes were analyzed using unconditional logistic regression analysis. RESULTS: Based on the results of univariate logistic regression, the risk of GBC was significantly and positively correlated with serum triglyceride, low-density lipoprotein, FINS, HOMA-IR, being female, BMI, DM, non-alcoholic fatty liver disease, and gallbladder stone disease (GSD), and significantly negatively correlated with high-density lipoprotein and FBG concentrations in serum, as well as hypertension. According to multivariate analysis, FINS was significantly positively associated with GBC risk, while DM showed an insignificant negative association; FBG was also not important. The most significant independent factor of GBC risk in patients with DM was HOMA-IR. Fasting blood glucose levels showed a significant negative relationship with GBC in patients with DM. In addition, this study indicated a significantly negative association between serum RBP levels and GBC. CONCLUSIONS: The findings of the current study revealed that the efficient treatment of insulin resistance is an important approach for decreasing GBC risk, as opposed to lowering blood sugar only, particularly in patients with DM. Interestingly, FBG may have had an inverse association with the development of GBC in patients with type 2 DM. Of note, the study found that a dramatic initial drop in RBP may help predict the occurrence of GBC.

Proteomic profiles and the function of RBP4 in endometrium during embryo implantation phases in pigs.

BACKGROUND: Endometrial receptivity plays a vital role in the success of embryo implantation. However, the temporal proteomic profile of porcine endometrium during embryo implantation is still unclear. RESULTS: In this study, the abundance of proteins in endometrium on days 9, 10, 11, 12, 13, 14, 15 and 18 of pregnancy (D9, 10, 11, 12, 13, 14, 15 and 18) was profiled via iTRAQ technology. The results showed that 25, 55, 103, 91, 100, 120, 149 proteins were up-regulated, and 24, 70, 169, 159, 164, 161, 198 proteins were down-regulated in porcine endometrium on D10, 11, 12, 13, 14, 15 and 18 compared with that on D9, respectively. Among these differentially abundance proteins (DAPs), Multiple Reaction Monitoring (MRM) results indicated that S100A9, S100A12, HRG and IFI6 were differentially abundance in endometrial during embryo implantation period. Bioinformatics analysis showed that the proteins differentially expressed in the 7 comparisons were involved in important processes and pathways related to immunization, endometrial remodeling, which have a vital effect on embryonic implantation. CONCLUSION: Our results reveal that retinol binding protein 4 (RBP4) could regulate the cell proliferation, migration and apoptosis of endometrial epithelial cells and endometrial stromal cells to affect embryo implantation. This research also provides resources for studies of proteins in endometrium during early pregnancy.

Lipocalin family proteins and their diverse roles in cardiovascular disease.

The lipocalin (LCN) family members, a group of small extracellular proteins with 160-180 amino acids in length, can be detected in all kingdoms of life from bacteria to human beings. They are characterized by low similarity of amino acid sequence but highly conserved tertiary structures with an eight-stranded antiparallel ß-barrel which forms a cup-shaped ligand binding pocket. In addition to bind small hydrophobic ligands (i.e., fatty acids, odorants, retinoids, and steroids) and transport them to specific cells, lipocalins (LCNs) can interact with specific cell membrane receptors to activate their downstream signaling pathways, and with soluble macromolecules to form the complex. Consequently, LCNs exhibit great functional diversity. Accumulating evidence has demonstrated that LCN family proteins exert multiple layers of function in the regulation of many physiological processes and human diseases (i.e., cancers, immune disorders, metabolic disease, neurological/psychiatric disorders, and cardiovascular disease). In this review, we firstly introduce the structural and sequence properties of LCNs. Next, six LCNs including apolipoprotein D (ApoD), ApoM, lipocalin 2 (LCN2), LCN10, retinol-binding protein 4 (RBP4), and Lipocalin-type prostaglandin D synthase (L-PGDS) which have been characterized so far are highlighted for their diagnostic/prognostic values and their potential effects on coronary artery disease and myocardial infarction injury. The roles of these 6 LCNs in cardiac hypertrophy, heart failure, diabetes-induced cardiac disorder, and septic cardiomyopathy are also summarized. Finally, their therapeutic potential for cardiovascular disease is discussed in each section.

Unraveling the role of resistin, retinol-binding protein 4 and adiponectin produced by epicardial adipose tissue in cardiac structure and function: evidence of a paracrine effect.

PURPOSE: Adipokines produced by adipose tissue have been found to be involved in the pathophysiology of metabolic and cardiovascular diseases. We aimed to investigate the relationships of resistin, retinol-binding protein 4 (RBP4) and adiponectin produced by epicardial adipose tissue with coronary artery disease (CAD) and cardiac structure and function. METHODS: Forty-one non-diabetic males scheduled for cardiothoracic surgery were examined. Anthropometric measurements, echocardiography, coronary angiography, and blood analysis were performed preoperatively. We measured the serum levels of resistin, RBP4, and adiponectin and their mRNA expression in thoracic subcutaneous adipose tissue and two epicardial adipose tissue samples, one close to left anterior descending artery (LAD) (resistin-LAD, RBP4-LAD, adiponectin-LAD), and another close to the right coronary artery (RCA) (resistin-RCA, RBP4-RCA, adiponectin-RCA). RESULTS: Left ventricular (LV) ejection fraction correlated negatively with adiponectin-LAD (rho = - 0.390, p = 0.025). The ratio of early to late diastolic transmitral flow velocity, as an index of LV diastolic function, correlated negatively with resistin-LAD (rho = - 0.529, p = 0.024) and RBP4-LAD (rho = - 0.458, p = 0.049). There was no difference in epicardial adipose tissue mRNA expression of resistin, RBP4, and adiponectin between individuals with CAD and those without CAD. When we compared the individuals with CAD in the LAD with those without CAD in the LAD, there was no difference in resistin-LAD, RBP4-LAD, and adiponectin-LAD. There was no difference in resistin-RCA, RBP4-RCA, and adiponectin-RCA between the individuals with CAD in the RCA and those without CAD in the RCA. CONCLUSION: Elevation of epicardial adipose tissue mRNA expression of adiponectin was associated with LV systolic dysfunction, while that of both resistin and RBP4 was linked to LV diastolic dysfunction.

Ovariectomy Increases Circulating Retinol-Binding Protein Concentrations Independently of Sex-Dependent Differences in Retinol Concentrations in Rats.

BACKGROUND: There is a sex-dependent difference in blood retinol and RBP concentrations, and plasma RBP is associated with insulin resistance. OBJECTIVES: We aimed to clarify sex-dependent variations in body concentrations of retinol and RBPs and their association with sex hormones in rats. METHODS: Plasma and liver retinol concentrations and hepatic mRNA and plasma concentrations of RBP4 were analyzed in 3- and 8-wk-old male and female Wistar rats before and after sexual maturity (experiment 1) and in orchiectomized male Wistar rats (experiment 2) and ovariectomized female Wistar rats (experiment 3). Furthermore, the mRNA and protein concentrations of RBP4 in adipose tissue were measured in ovariectomized female rats (experiment 3). RESULTS: There were no sex-dependent differences in liver retinyl palmitate and retinol concentrations; however, the plasma retinol concentration was significantly higher in male rats than that in female rats after sexual maturity. Furthermore, the plasma retinol concentrations did not differ between the ovariectomized or orchiectomized rats and the control rats. Plasma Rbp4 mRNA concentrations were higher in male rats than those in female rats but not in castrated and control rats, a change consistent with plasma retinol concentration. Plasma RBP4 concentrations were also higher in male rats than those in female rats; however, unlike liver Rbp4 gene expression, plasma RBP4 concentrations were 7-fold higher in the ovariectomized rats than those in the control rats. Moreover, the Rbp4 mRNA concentrations in inguinal white adipose tissue was significantly higher in the ovariectomized rats than those in the control rats and correlated with plasma RBP4 concentrations. CONCLUSIONS: Hepatic Rbp4 mRNA is higher in male rats through a sex hormone-independent mechanism, which may contribute to sex differences in blood retinol concentrations. Furthermore, ovariectomy leads to an increase in adipose tissue Rbp4 mRNA and blood RBP4 concentrations, which may contribute to insulin resistance in ovariectomized rats and postmenopausal women.

Visceral adipose tissue-directed human kallistatin gene therapy improves adipose tissue remodeling and metabolic health in obese mice.

OBJECTIVE: Adipose tissue remodeling is a dynamic process that is pathologically expedited in the obese state and is closely related to obesity-associated disease progression. This study aimed to explore the effects of human kallistatin (HKS) on adipose tissue remodeling and obesity-related metabolic disorders in mice fed with a high-fat diet (HFD). METHODS: Adenovirus-mediated HKS cDNA (Ad.HKS) and a blank adenovirus (Ad.Null) were constructed and injected into the epididymal white adipose tissue (eWAT) of 8-weeks-old male C57B/L mice. The mice were fed normal or HFD for 28 days. The body weight and circulating lipids levels were assessed. Intraperitoneal glucose tolerance test (IGTT) and insulin tolerance test (ITT) were also performed. Oil-red O staining was used to assess the extent of lipid deposition in the liver. Immunohistochemistry and HE staining were used to measure HKS expression, adipose tissue morphology, and macrophage infiltration. Western blot and qRT-PCR were used to evaluate the expression of adipose function-related factors. RESULTS: At the end of the experiment, the expression of HKS in the serum and eWAT of the Ad.HKS group was higher than in the Ad.Null group. Furthermore, Ad.HKS mice had lower body weight and decreased serum and liver lipid levels after four weeks of HFD feeding. IGTT and ITT showed that HKS treatment maintained balanced glucose homeostasis. Additionally, inguinal white adipose tissue (iWAT) and eWAT in Ad.HKS mice had a higher number of smaller-size adipocytes and had less macrophage infiltration than Ad.Null group. HKS significantly increased the mRNA levels of adiponectin, vaspin, and eNOS. In contrast, HKS decreased RBP4 and TNFα levels in the adipose tissues. Western blot results showed that local injection of HKS significantly upregulated the protein expressions of SIRT1, p-AMPK, IRS1, p-AKT, and GLUT4 in eWAT. CONCLUSIONS: HKS injection in eWAT improves HFD-induced adipose tissue remodeling and function, thus significantly improving weight gain and dysregulation of glucose and lipid homeostasis in mice.

Evaluation of maternal serum SERPINC1, E-selectin, P-selectin, RBP4 and PP13 levels in pregnancies complicated with preeclampsia.

OBJECTIVE: The aim of this study is to investigate whether Serpin clade C (SERPINC1), E-selectin, P-selectin, Placental protein 13 (PP13), and Retinol-binding protein-4 (RBP4) levels in maternal serum were associated with the presence of preeclampsia and to compare them with uncomplicated pregnancies. METHODS: This prospective study included 40 women with preeclampsia and 40 healthy pregnant women. An enzyme-linked immunosorbent assay kit was used to measure serum SERPINC1, E-selectin, P-selectin, PP13, and RBP4 levels. RESULTS: The preeclampsia group had significantly higher E-selectin and P-selectin levels than the control group. PP13 and SERPINC1 levels were also significantly lower than the control group. There was no significant difference in RBP4 levels. The receiver operating characteristic curve revealed the best cutoff values for the following: E-selectin >19.2 ng/mL, with 87.5% sensitivity and 95% specificity; P-selectin >5.1 ng/mL, with 97.5% sensitivity and 100% specificity; PP13 ≤ 107.03 pg/mL, with 72.5% sensitivity and 77.5% specificity; and SERPINC1 ≤ 87.76 ng/mL, with 100% sensitivity and 97.5% specificity. CONCLUSION: In this study, the endothelial dysfunction parameters SERPINC1, PP13, E-selectin, and P-selectin were found to be associated with preeclampsia. Endothelial dysfunction biomarkers in maternal non-serum body fluids may differ. More research is needed, especially to determine the relationship between SERPINC1 and preeclampsia.

Exosomal RBP4 potentiated hepatic lipid accumulation and inflammation in high-fat-diet-fed mice by promoting M1 polarization of Kupffer cells.

Exosomes containing various biological cargoes have potential to be novel diagnostic biomarkers for metabolic diseases. In this study, retinol-binding protein 4 (RBP4) was found to be enriched in serum exosomes, and its increased levels could be considered as an independent risk factor for the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Exosomal RBP4 (exo-RBP4), primarily derived from hepatocytes, significantly enhanced the M1-like polarization of Kupffer cells (KCs) via promoting the activation of NOX2 and NF-κB and reactive oxygen species (ROS) accumulation, resulting in the over-production of inflammatory cytokines including TNF-α. Subsequently, those excess cytokines remarkably increased the levels of intracellular free fatty acid uptake and lipogenesis-related genes (FAS and SREBP-1c) but decreased fatty acid degradation-related genes (CPT-1 and PPARα) in palmitic acid-treated LO2 cells. More notably, TNF-α significantly elevated RBP4 transcription by activating STAT3 in hepatocytes, playing a positive role in NAFLD development. Intravenous injection with RBP4 (50 µg/kg) potentiated hepatic lipid accumulation, M1-type KC proportion, and serum pro-inflammatory cytokine levels in the hepatic tissues of high-fat-diet-fed mice. Collectively, these data indicated that exo-RBP4 converted KCs to M1 subtype by mediating the NOX2/ROS/NF-κB pathway, subsequently promoting de novo lipogenesis in hepatocytes by TNF-α secretion to activate the JAK2/STAT3 signaling pathway. Therefore, this study uncovered a novel intercellular communication between the inflammatory microenvironment and lipid metabolism for fostering NAFLD progression and found the potential of exo-RBP4 as a novel diagnostic biomarker and therapeutic target for NAFLD.

The effect of dietary carbohydrate restriction and aerobic exercise on retinol binding protein 4 (RBP4) and fatty acid binding protein 5 (FABP5) in middle-aged men with metabolic syndrome.

Exercise and dietary interventions have been described to positively affect metabolic syndrome (MetS) via molecular-induced changes. The purpose of this study was to investigate the effects of dietary carbohydrate restriction and aerobic exercise (AE) on retinol binding protein 4 (RBP4) and fatty acid binding protein 5 (FABP5) in middle-aged men with MetS. The study had a randomised, double-blinded, parallel-controlled design. Forty middle-aged men with MetS (age: 53·97 ± 2·85 years, BMI = 31·09 ± 1·04 kg/m2) were randomly assigned to four groups, AE (n 10), ketogenic diet (KD; n 10), AE combined with KD (AE + KD; n 10) or control (C; n 10). RBP4, FABP5, body composition (body mass, BMI and body fat), insulin resistance, insulin sensitivity and MetS factors were evaluated prior to and after the 12-week intervention. AE + KD significantly decreased the body fat percentage (P = 0·006), BMI (P = 0·001), Zmets (P = 0·017), RBP4 (P = 0·017) and the homeostasis model of insulin resistance (HOMA-IR) (P = 0·001) as compared with control group and marginally significantly decreased the Zmets as compared with exercise group (P = 0·086). KD significantly decreased RBP4 levels as compared with control group (P = 0·041). Only the AE intervention (P = 0·045) significantly decreased FABP5 levels. Combining intervention of carbohydrate restriction with AE compared with carbohydrate restriction and AE alone improved RBP4, HOMA-IR as well as different body composition and MetS factors in middle-aged men with MetS.

Does Retinol-Binding Protein 4 (holo- and apo-RBP4) Increase or Remain Constant in Sera from Patients with Hypothyroidism?

Retinol-binding protein 4 (RBP4) is a retinol transporter in the blood plasma. Many diseases alter the plasma or serum levels of RBP4. Since serum RBP4 concentrations have been reported to decrease in hyperthyroidism, this study investigated whether serum RBP4 concentrations increased or remained constant in hypothyroidism. In sera from patients with hypothyroidism (n=71), hyperthyroidism (n=30), and healthy subjects (n=20), serum concentrations of RBP4 (sum of holo- and apo-RBP4), retinol, albumin, creatinine, and related constituents were measured, and RBP4/retinol molar ratio (as an index of apo-RBP4) and estimated glomerular filtration rate (eGFR) were calculated. The results showed that serum RBP4 concentrations tended to increase with decreasing free thyroxine concentrations, but there were no significant differences among patients with hypothyroidism, hyperthyroidism, and healthy subjects. When patients with hypothyroidism were subdivided by serum RBP4 level using 2.1 µmol/L cut-off value, patients with >2.1 µmol/L were revealed to be patients with older age having lower tri-iodothyronine, higher holo-RBP4, higher apo-RBP4, higher retinol, higher RBP4/retinol molar ratio, and lower eGFR than those in patients with <2.1 µmol/L. Multiple regression analysis showed significant associations between serum RBP4 levels and explanatory variables (retinol and eGFR). Although serum levels of RBP4 prior to the onset of renal dysfunction may affect the present concentrations, we conclude that the increase of serum RBP4 (both holo- and apo-RBP4) in patients with hypothyroidism was attributed to the decline in eGFR. In contrast, serum RBP4 concentration remained constant without renal dysfunction.

Association between Retinol-Binding Protein 4 Levels and Preeclampsia: A Systematic Review and Meta-Analysis.

Retinol-binding protein 4 (RBP4) is claimed to be associated with the development of preeclampsia, yet the reports are inconclusive. This systematic review and meta-analysis aimed to assess the association between RBP4 levels and preeclampsia. The PubMed, Google Scholar and ScienceDirect databases were searched for studies that investigated RBP4 levels in preeclampsia patients and compared them with normal controls. The meta-analysis was conducted by calculating the standardized mean difference (SMD) of RBP4 between cases and controls. The meta package with the R software was used to perform all statistical analysis. A total of 13 studies, comprising 569 cases and 1411 controls, met the inclusion criteria and were thus included in the meta-analysis. According to the random effect model, the SMD of RBP4 was significantly higher in women with preeclampsia compared with normal controls [SMD of RBP4: 0.55 ng/mL; 95% CI (0.06; 1.05); p = 0.028; I2 = 89%]. Likewise, the stratified meta-analysis showed the same pattern in the studies which measured RBP4 levels in the third trimester, as well as in the studies that investigated severe preeclampsia. Meta-regression did not identify any factor that significantly affected the overall estimate. There was no evidence of reporting bias (Egger's test; t = 0.43; p = 0.587). This meta-analysis with high heterogeneity showed that higher levels of RBP4 were associated with preeclampsia risk. More longitudinal studies spanning the three trimester periods are needed to clarify the association of RBP4 and its dynamics in preeclampsia cases throughout pregnancy.

Products of the visual cycle are detected in mice lacking retinol binding protein 4, the only known vitamin A carrier in plasma.

Efficient delivery of vitamin A to the retinal pigment epithelium is vital to the production of the light-sensitive visual chromophore 11-cis-retinal. Nevertheless, retinol binding protein 4 (RBP4) is the only known carrier of vitamin A in plasma. Here, we present new findings that further characterize the visual cycle in the presence of Rbp4 deficiency. In the face of impaired delivery of retinol in Rbp4-/- mice, we determined that 11-cis-retinaldehyde reached levels that were ∼60% of WT at 4 months of age and all-trans-retinyl ester was 18% of normal yet photoreceptor cell loss was apparent by 8 months of age. The lack of Rbp4 appeared to have a greater impact on scotopic rod-mediated responses than on cone function at early ages. Also, despite severely impaired delivery of retinol, bisretinoid lipofuscin that forms as a byproduct of the visual cycle was measurable by HPLC and by quantitative fundus autofluorescence. In mice carrying an Rpe65 amino acid variant that slows visual cycle kinetics, Rbp4 deficiency had a less pronounced effect on 11-cis-retinal levels. Finally, we found that ocular retinoids were not altered in mice expressing elevated adipose-derived total Rbp4 protein (hRBP4+/+AdiCre+/-). In conclusion, our findings are consistent with a model in which vitamin A can be delivered to the retina by Rbp4-independent pathways.

Network Pharmacology and Transcriptomics Reveal the Mechanism of GuaLouQuMaiWan in Treatment of Type 2 Diabetes and Its Active Small Molecular Compound.

The main pathophysiological abnormalities in type 2 diabetes (T2D) include pancreatic ß-cell dysfunction and insulin resistance. Due to hyperglycemia, patients receive long-term treatment. However, side effects and drug tolerance usually lead to treatment failure. GuaLouQuMaiWan (GLQMW), a common traditional Chinese medicine (TCM) prescription, has positive effects on controlling blood sugar and improving quality of life, but the mechanism is still unclear. To decipher their molecular mechanisms, we used a novel computational systems pharmacology-based approach consisting of bioinformatics analysis, network pharmacology, and drug similarity comparison. We divided the participants into nondisease (ND), impaired glucose tolerance (IGT), and type 2 diabetes groups according to the WHO's recommendations for diabetes. By analyzing the gene expression profile of the ND-IGT-T2D (ND to IGT to T2D) process, we found that the function of downregulated genes in the whole process was mainly related to insulin secretion, while the upregulated genes were related to inflammation. Furthermore, other genes in the ND-IGT (ND to IGT) process are mainly related to inflammation and lipid metabolic disorders. We speculate that 17 genes with a consistent trend may play a key role in the process of ND-IGT-T2D. We further performed target prediction for 50 compounds in GLQMW that met the screening criteria and intersected the differentially expressed genes of the T2D process with the compounds of GLQMW; a total of 18 proteins proved potential targets for GLQMW. Among these, RBP4 is considerably related to insulin resistance. GO/KEGG enrichment analyses of the target genes of GLQMW showed enrichment in inflammation- and T2D therapy-related pathways. Based on the RDKit tool and the DrugBank database, we speculate that (-)-taxifolin, dialoside A_qt, spinasterol, isofucosterol, and 11,14-eicosadienoic acid can be used as potential drugs for T2D via molecular docking and drug similarity comparison.