Adiponectin Research Articles

Changes in adiponectin system after ventricular assist device in pediatric heart failure

Ventricular assist device (VAD) implant represents a therapeutic option for pediatric patients with end-stage heart failure (HF). Heart unloading by VAD can modify several molecular pathways underlying cardiac function in HF. Among them, the potential role of microRNA (miRNAs) in response to VAD implant is emerging. This study was aimed at investigating in HF pediatric patients the effect of VAD-modified miRNAs on the adiponectin (ADPN) system, known to exert cardioprotective actions. ADPN was measured in plasma samples obtained from HF children, before and 1month after VAD implant, and from healthy control children. miRNA profile and molecules belonging to ADPN system were determined in cardiac biopsies collected at the time of VAD implantation (pre-VAD) and at the moment of heart transplant (post-VAD). An in vitro study using HL-1 cell line was performed to verify the regulatory role of the VAD-modified miRNA on the ADPN system. VAD implant did not affect circulating and cardiac levels of ADPN, but increased the cardiac mRNA expression of ADPN receptors, including AdipoR1, AdipoR2, and T-cad. AdipoR2 and T-cad were inversely related to the VAD-modified miRNA levels. The in vitro study confirmed the regulatory role of miR-1246 and miR-199b-5p on AdipoR2, and of miR-199b-5p on T-cad. These data suggest that VAD treatment could regulate the expression of the cardioprotective ADPN system by epigenetic mediators, suggesting that miRNAs have a potential role as therapeutic targets to improve cardiac function in HF pediatric patients.

The Polymorphism rs17300539 in the Adiponectin Promoter Gene Is Related to Metabolic Syndrome, Insulin Resistance, and Adiponectin Levels in Caucasian Patients with Obesity.

Background and Aims: The present study was designed to investigate SNP rs17300539 in the ADIPOQ gene and its relationships with obesity, metabolic syndrome (MS), and serum circulating adiponectin. Methods: The present design involved a Caucasian population of 329 subjects with obesity. Anthropometric and adiposity parameters, blood pressure, biochemical parameters, and the percentage of patients with metabolic syndrome were recorded. The ADIPOQ gene variant (rs17300539) genotype was evaluated. Results: The percentage of patients with different genotypes of the rs17300539 polymorphism in this sample was 86.0% (n = 283) (GG), 11.2% (n = 37) (GA), and 2.7% (n = 9) (AA). The allele frequency was G (0.76) and A (0.24). Applying the dominant genetic model (GG vs. GA + AA), we reported differences between genotype GG and genotype GA + AA for serum adiponectin levels (Delta: 7.5 ± 1.4 ng/mL; p = 0.03), triglycerides (Delta: 41.1 ± 3.4 mg/dL; p = 0.01), fastingcirculating insulin (Delta: 4.9 ± 1.1 mUI/L; p = 0.02), and insulin resistance as HOMA-IR (Delta: 1.4 ± 0.1 units; p = 0.02). The remaining biochemical parameters were not related to the genotype of obese patients. The percentages of individuals with MS (OR = 2.07, 95% CI = 1.3-3.88; p = 0.01), hypertriglyceridaemia (OR = 2.66, 95% CI = 1.43-5.01; p = 0.01), and hyperglycaemia (OR = 3.31, 95% CI = 1.26-8.69; p = 0.02) were higher in GG subjects than patients with A allele. Logistic regression analysis reported an important risk of the presence of metabolic syndrome in GG subjects (OR = 1.99, 95% CI = 1.21-4.11; p = 0.02) after adjusting for adiponectin, dietary energy intakes, gender, weight, and age. Conclusions: The GG genotype of rs17300539 is associated with hypertriglyceridaemia, insulin resistance, low adiponectin levels, and a high risk of metabolic syndrome and its components.

Relationship of Adiponectin and High-Sensitivity CReactive Protein with Left Ventricular Dysfunction among Patients Undergoing Coronary Angiography

Background: Decreased levels of adiponectin (APN) and elevated levels of high-sensitivity C-reactive protein (hs-CRP) have been found as predictors of left ventricular dysfunction and cardiovascular events. Therefore, this study aimed to assess the relationship of APN and hs-CRP with the severity of left ventricular dysfunction among Egyptian patients undergoing coronary angiography (CAG).
 Methods: A cross-sectional study was conducted among 100 Egyptian patients who underwent clinically indicated CAG at Suez Canal University Hospital in Ismailia - Egypt, from May 2009 to December 2010. The left ventricular ejection fraction (LVEF) scoring system was used to assess left ventricular function based on echocardiographic findings. Pearson correlation was used to determine the relationship of APN and hs-CRP levels with echocardiographic LVEF score, and analysis of variance (ANOVA) was used to compare clinical and biochemical parameters among patients according to left ventricular function at P-value <0.05.
 Results: The mean hs-CRP level had a significant weak negative correlation with the mean HDL-cholesterol level (r = -0.222; P = 0.048), while the mean APN level had a significant weak negative correlation with BMI (r = -0.269; P = 0.007) but a significant weak positive correlation with the mean hs-CRP level (r = 0.215; P = 0.031) and a significant moderate positive correlation with the mean HDL-cholesterol level (r = 0.302; P = 0.002). Left ventricular function in patients undergoing CAG was normal in 34 (34%), mildly impaired in 41 (41%) patients and moderately impaired in 25 (25%), with significantly different mean hs-CRP levels among the three groups (P = 0.025) that increased from normal to moderately impaired left ventricular function. However, there was no statistically significant difference in left ventricular function according to the mean level of APN.
 Conclusion: The hs-CRP level is negatively correlated with HDL-cholesterol, while APN is negatively correlated with BMI and hs-CRP but positively correlated with HDL-cholesterol in Egyptian patients undergoing CAG. The hs- CRP level correlates with the severity of left ventricular dysfunction. However, left ventricular function does not appear to correlate with APN levels.

Adiponectin inhibits LPS-induced nucleus pulposus cell pyroptosis through the miR-135a-5p/TXNIP signaling pathway.

Pyroptosis, a newly discovered programmed cell death process, is characterized by NLRP3 inflammasome activation and pro-inflammatory mediator release. Nucleus pulposus (NP) cell pyroptosis is an important cause of intervertebral disc degeneration (IDD). Adiponectin (APN) is an adipokine and has an anti-inflammatory effect. However, whether and how APN protects against NP cell pyroptosis remains unexplored. Our results showed that human degenerated NP tissue displayed a significant increase in the protein levels of NLRP3, caspase-1 and GSDMD-N. APN expression was down-regulated in human degenerated NP tissue and NP cells challenged with lipopolysaccharide (LPS). Lentivirus-mediated overexpression of APN increased miR-135a-5p levels, decreased thioredoxin-interacting protein (TXNIP) expression and its interaction with NLRP3, and inhibited pyroptosis in human NP cells stimulated with LPS. TXNIP was identified as a direct target of miR-135a-5p. The inhibitory effects of APN on pyroptosis were reversed by pretreatment with miR-135a-5p inhibitor or lentiviral vector expressing TXNIP in LPS-treated human NP cells. In summary, these data suggest that APN restrains LPS-induced pyroptosis through the miR-135a-5p/TXNIP signaling pathway in human NP cells. Increasing APN levels could be a new approach to retard IDD.

Intracerebroventricular Injection of MHY1485 Blocked the Beneficial Effect of Adiponectin on Aversive Memory in the STZ Model of Dementia.

The most prominent adipokine, adiponectin (APN), has an adverse relationship with the malfunction of adipose tissue. Obesity causes a decrease in plasma APN levels, which eventually results in insulin resistance and diabetes. In this study, we assessed how the effects of APN on memory are influenced by the insulin receptor substrate-1 (IRS-1) and the mammalian target of rapamycin (mTOR) pathways. Streptozotocin (STZ) 3 mg/kg intracerebroventricular injections on days 1 and 3 following cannulation were used to create an animal model of Alzheimer's disease. The acquisition phase was preceded by injections of MHY and adiponectin. For the passive avoidance task, the stepthrough latency and total duration in the dark compartment were recorded and evaluated, and the preference index was calculated for the novel object identification test. IRS-1 protein expression in the hippocampus was assessed by western blotting. STZ reduced the step-through latency (STL), which rose significantly (P≤0.001) in the APN+STZ group. The memory-improving effects of APN were reversed when MHY was administered first (P≤0.001). The STZ and APN+STZ+MHY groups both had a substantial decline in the preference index (P≤0.01). Compared to the control group, the STZ group's expression of the IRS- 1 protein was dramatically reduced (P≤0.0001). In contrast to the APN+STZ group, the MHYtreated group likewise showed decreased IRS-1 protein expression (P≤0.0001), but APN+STZ was able to enhance IRS-1 expression rate (P≤0.0001). In a rat model of AD, we found that adiponectin improved aversive and cognitive memory, which is at least partially mediated by the mTOR signaling cascade.

Effect of Chiglitazar and Sitagliptin on Bone Mineral Density and Body Composition in Untreated Patients with Type 2 Diabetes.

To evaluate the changes in bone mineral density (BMD) and body composition in untreated patients with type 2 diabetes mellitus (T2DM) before and after chiglitazar or sitagliptin treatment. A total of 81 patients with T2DM were randomly divided to receive chiglitazar or sitagliptin treatment for 24 weeks (54 in the chiglitazar group and 27 in the sitagliptin group). We measured the spine lumbar BMD, hip BMD, fat mass (FM), fat-free mass (FFM), percent body fat (%BF), android FM, gynoid FM and skeleton muscle mass (SMM) using dual-energy X-ray absorptiometry (DEXA) and examined serum adiponectin (ADP) levels at baseline and the end of the study. There were no significant changes in the BMD of the L2-4, femoral neck, trochanter or total hip as well as in the BMC after 24 weeks of treatment with chiglitazar or sitagliptin. After chiglitazar administration, the FM, gynoid FM and gynoid to total FM ratio were higher, while the android to total FM ratio and the android to gynoid FM ratio (AOI) were significantly lower. Sitagliptin intervention did not result in statistically significant differences in total fat loss, but it did cause significant decreases in %BF and AOI as well as increases in the FFM, gynoid to total FM ratio and SMM. The ADP levels had significantly negative associations with AOI in all eligible patients. The chiglitazar had no deleterious effects on BMD and resulted in body fat redistribution in untreated patients with T2DM. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02173457).

Osteocalcin activates lipophagy via the ADPN-AMPK/PPARα-mTOR signaling pathway in chicken embryonic hepatocyte

Fatty liver hemorrhage syndrome (FLHS) is the leading cause of noninfectious mortality in caged layers worldwide. Osteocalcin (OCN) is a protein secreted by osteoblasts, and its undercarboxylated form (ucOCN) acts as a multifunctional hormone that protects laying hens from FLHS. Lipophagy is a form of selective autophagy that breaks down lipid droplets (LDs) through lysosomes, and defective lipophagy is associated with FLHS. The aim of this study was to investigate the effects of ucOCN on the lipophagy of chicken embryonic hepatocytes and associated the function of the adiponectin (ADPN) signaling pathway. In this study, chicken embryonic hepatocytes were divided into 5 groups: control (CONT), fat emulsion (FE, 10% FE, v/v), FE with ucOCN at 1 ng/mL (FE-LOCN), 3 ng/mL (FE-MOCN), and 9 ng/mL (FE-HOCN). In addition, 4 μM AdipoRon, an adiponectin receptor agonist, was used to investigate the function of ADPN. The results showed that compared with CONT group, FE promoted the levels of phosphorylation of mammalian target of rapamycin (p-mTOR) (P < 0.05) and decreased the mRNA expression of ADNP receptors (AdipoR1 and AdipoR2). Compared with FE group, 3 and 9 ng/mL ucOCN inhibited the levels of autophagy adaptor p62 and p-mTOR (P < 0.05), increased the ratios of LC3-II/LC3-I (P < 0.05) and phosphorylated adenosine 5'-monophosphate-activated protein kinase (p-AMPK)/AMPK (P < 0.05), as well as the levels of peroxisome proliferator-activated receptor α (PPAR-α) and ADPN (P < 0.05). In addition, ucOCN at the tested concentrations increased the colocalization of LC3 and LDs in fatty hepatocytes. Administrated 4 μM AdipoRon activated AdipoR1 and AidpoR2 mRNA expression (P < 0.05), decreased the concentrations of triglyceride (P < 0.05), without effects on cell viability (P > 0.05). AdipoRon also increased the LC3-II/LC3-I ratio (P < 0.05) and the levels of p-AMPK/AMPK and PPAR-α (P < 0.05). In conclusion, the results reveal that ucOCN regulates lipid metabolism by activating lipophagy via the ADPN-AMPK/PPARα-mTOR signaling pathway in chicken embryonic hepatocytes. The results may provide new insights for controlling FLHS in laying hens.

LEP (G2548A-G19A) and ADIPOQ (T45G-G276T) gene polymorphisms are associated with markers for metabolic syndrome

Background and aimsThere is a link between genetics with metabolic balance and adiposity homeostasis on metabolic syndrome (MetS). Polymorphism in adipokine genes such as leptin and adiponectin may play an important role in its development. This study aimed to determine the association of the individual and general components of MetS with genetic alterations in LEP (rs7799039 and rs2167270) and ADIPOQ (rs1501299 and rs2241766) genes in the Mexican population.Methods and resultsThe polymorphisms of the LEP gene rs7799039 and rs2167270, together with rs1501299 and rs2241766 polymorphisms of the ADIPOQ gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 328 individuals (n = 131 MetS). The rs7799039 under the recessive inheritance model was found to be associated with increased risk of MetS (OR = 2.16, 95% CI = 1.06–4.37), dyslipidemia (OR = 7.97, 95% CI = 2.17–29.36), low HDL (OR = 7.01, 95% CI = 1.65–29.71) and hypertension (OR = 13.02, 95% CI = 1.76–96.44); the heterozygote demonstrate a protective effect on MetS (OR = 0.48, 95% CI = 0.28–0.88) and diabetes (OR = 0.09, 95% CI = 0.02–0.53) under the over the dominant model. Haplotype analysis showed linkage disequilibrium between the SNPs of ADIPOQ rs1501299/rs2241766, and their association as risk factors for low HDL and hypertension.ConclusionThe association of rs7799039 with the presence of MetS, suggests a risk factor for the development of dyslipidemia, as well as its heterozygous as a protective factor for DM. There is a linkage disequilibrium between the SNPs of ADIPOQ.

Linking Adiponectin and Its Receptors to Age-Related Macular Degeneration (AMD).

In recent years, there has been a captivating focus of interest in elucidating the intricate crosstalk between adiponectin (APN), a versatile fat-associated adipokine and ocular pathologies. Unveiling the intricate relationship between adipocytokine APN and its receptors (AdipoRs) with aging eye disorders has emerged as a fascinating frontier in medical research. This review article delves into this connection, illuminating the hidden influence of APN on retinal health. This comprehensive review critically examines the latest findings and breakthroughs that underscore the pivotal roles of APN/AdipoRs signaling in maintaining ocular homeostasis and protecting against eye ailments. Here, we meticulously explore the intriguing mechanisms by which APN protein influences retinal function and overall visual acuity. Drawing from an extensive array of cutting-edge studies, the article highlights APN's multifaceted functions, ranging from anti-inflammatory properties and oxidative stress reduction to angiogenic regulation within retinal and macula tissues. The involvement of APN/AdipoRs in mediating these effects opens up novel avenues for potential therapeutic interventions targeting prevalent aging eye conditions. Moreover, this review unravels the interplay between APN signaling pathways and age-related macular degeneration (AMD). The single-cell RNA-seq results validate the expression of both the receptor isoforms (AdipoR1/R2) in retinal cells. The transcriptomic analysis showed lower expression of AdipoR1/2 in dry AMD pathogenesis compared to healthy subjects. The inhibitory adiponectin peptide (APN1) demonstrated over 75% suppression of CNV, whereas the control peptide did not exert any inhibitory effect on choroidal neovascularization (CNV). The elucidation of these relationships fosters a deeper understanding of adipose tissue's profound influence on ocular health, presenting new prospects for personalized treatments and preventative measures. Because APN1 inhibits CNV and leakage, it can be used to treat human AMD, although the possibility to treat human AMD is in the early stage and more clinical research is needed. In conclusion, this review provides a captivating journey into the enthralling world of APN, intertwining the realms of adipose biology and ophthalmology in aging.

ADIPOQ gene (T45G and G276T) single nucleotide polymorphisms and their association with gestational diabetes mellitus in a Filipino population

Several studies have associated the presence of ADIPOQ gene polymorphisms with insulin resistance, adiponectin levels, and metabolic diseases such as diabetes, although with varying degrees of correlation depending on ethnicity. Here we aim to identify individual’s susceptibility to gestational diabetes mellitus (GDM) in the presence of T45G and G276T single nucleotide polymorphisms (SNPs) within the ADIPOQ gene among Filipino pregnant women. A total of 285 pregnant women (95 GDM cases and 190 controls) were included in this study. Two ADIPOQ gene polymorphisms were genotyped using TaqMan assay. Results of SNP genotyping showed no significant differences in the frequencies of TT, TG and GG genotypes of T45G SNP between the GDM and control group [p = 1.0000, 0.6179, 0.5797; OR (95%CI) = 1.030 (0.582–1.874), 1.135 (0.683–1.828), 0.833 (0.481–1.420)]. Similarly, the frequencies of GG, GT, and TT genotypes of G276T SNP were comparable in both groups [p = 0.8002, 1.0000, 0.3466; OR (95%CI) = 1.090 (0.654–1.785), 1.022 (0.616–1.665), 0.433 (0.092–1.698)]. Moreover, although adiponectin levels were significantly decreased in GDM group (p = 0.0196) and have shown substantial negative correlations with FBS, 1-hour OGTT, 2-hour OGTT, and HOMA-IR (p < 0.05), they were not significantly different according to genotypes of T45G and G276T polymorphisms both in GDM and control group. Our results suggest that neither of the two ADIPOQ gene polymorphisms influence adiponectin levels and development of GDM in a Filipino population.

Antidepressant-like effects of Jieyu Chufan capsules in the olfactory bulbectomy rat model

The olfactory bulbectomy (OBX) animal model of depression reproduces the behavioral and neurochemical changes observed in depressed patients. We assessed the therapeutic effects of the Jieyu Chufan (JYCF) capsule on OBX rats. JYCF ameliorated the hedonic and anxiety-like behavior of OBX rats and attenuated the cortical and hippocampal damage. JYCF enhanced the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2), and adiponectin (ADPN) in the cortex and hippocampus of OBX rats. JYCF also reduced cortisol levels and restored the levels of excitatory neurotransmitters, such as 5-hydroxytryptamine (5-HT), acetylcholine (ACH), and glutamic acid (Glu), in the brain tissue of OBX rats. Our results suggest that JYCF preserves the synaptic structure by increasing the levels of synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) and alleviates the histological alterations of brain tissue by activating AKT/PKA-CREB-BDNF pathways, and by upregulating ADPN and FGF2 expression in OBX rats. JYCF exerts multiple therapeutic effects on depression, including modulating neurotransmitters, repairing neuronal damage, and maintaining synaptic integrity. These findings support the potential of JYCF as a novel antidepressant agent with therapeutic effects on depression and related neurological disorders.

Abstract 175: Adiponectin Alleviates Cortical Neuronal Apoptosis Following Cardiopulmonary Resuscitation by Attenuating MiR-31-5p Carried by Brain Microvascular Endothelial Cell-Derived Extracellular Vesicles

Background: Adiponectin (APN) is a cardiovascular-protective adipokine. Our previous research has shown that APN administration reduced cortical neuron apoptosis in mice after resuscitation. Brain microvascular endothelial cell-derived extracellular vesicles (BMEC-sEVs) have neuroprotective properties, and APN regulates BMEC-sEVs' function to alleviate neuronal apoptosis after resuscitation. However, the specific molecular mechanisms are unclear. MicroRNAs carried by sEVs play essential roles. Hypothesis: APN may alleviate cortical neuron apoptosis by regulating miRNAs carried by BMEC-sEVs. Aims: To investigate if APN attenuates cortical neuron apoptosis in mice after resuscitation by regulating BMEC-sEVs-miRNAs and to elucidate the underlying molecular mechanisms. Methods: BMEC-sEVs APN were extracted and identified. BMEC-sEVs were injected into the brain to establish a cardiopulmonary resuscitation mouse model, and cortical neuron apoptosis was assessed. Co-culture experiments were performed between BMEC-sEVs and primary cortical neurons, and apoptosis was evaluated after oxygen-glucose deprivation/reperfusion (OGD/R). Bioinformatics identified miRNAs with pro-apoptotic effects. APN-regulated specific BMEC-sEV miRNAs were screened. Overexpression and inhibition experiments confirmed the neuroprotective effects of the identified miRNA. Target genes were screened, and downstream signaling pathways were explored. Results: APN enhanced the protective effect of BMEC-sEVs against cortical neuron apoptosis. APN preconditioning reduced miR-155-5p and miR-31-5p levels in BMEC-sEVs APN . MiR-31-5p was highly expressed in primary BMECs and increased after OGD/R. Overexpression of miR-31-5p in cortical neurons aggravated neuronal apoptosis. Inhibition of miR-31-5p reduced apoptotic neurons in Adipoq -/- mice after ROSC. Map3k1 was the most affected target gene of miR-31-5p, and its regulatory role in cortical neuron apoptosis was confirmed. Conclusion: APN alleviates cortical neuron apoptosis after resuscitation by downregulating miR-31-5p expression in BMEC-sEVs; BMEC-sEVs APN alleviate cortical neuron apoptosis through the miR-31-5p/MAP3K1 signaling pathway.

Progress in Research on Biomarkers of Gestational Diabetes Mellitus and Preeclampsia.

Gestational diabetes mellitus (GDM) and preeclampsia (PE) are common complications in pregnancy, with incidence rates of 1-5% and 9.4%, respectively, in China. Both these phenomena can cause adverse pregnancy outcomes and are extremely harmful to the mother and fetus. In this study, we observed that several predictive factors have important value in GDM and PE. Among the GDM group, abnormal levels of adiponectin (APN), C-reactive protein (CRP), and Leptin were observed. The coexistence of PE and GDM in the pregnant population is not uncommon. Ultimately, we discovered abnormal levels of factors such as Visfatin, Advanced oxidative protein product (AOPP), Fibroblast growth factor 21 (FGF21), and resistin in both GDM and PE groups. Particularly, the FGF21 factor holds significant importance in our research. Therefore, we need to complete the analysis and discussion of relevant predictive factors to enable early prediction and disease monitoring of GDM, PE, and other pregnancy-related disorders, ultimately contributing to the long-term health of pregnant women.

A Prediction Model for Sight-Threatening Diabetic Retinopathy Based on Plasma Adipokines among Patients with Mild Diabetic Retinopathy.

Accumulating evidence has suggested a link between adipokines and diabetic retinopathy (DR). This study is aimed at investigating the risk factors for sight-threatening DR (STDR) and establishing a prognostic model for predicting STDR among a high-risk population of patients with type 2 diabetes mellitus (T2DM). Plasma concentrations of adipokines were determined by enzyme-linked immunosorbent assay. In the case-control set, principal component analysis (PCA) was performed to select optimal predictive cytokines for STDR, involving severe nonproliferative DR (NPDR) and proliferative DR. Support vector machine (SVM) was used to examine the possible combination of baseline plasma adipokines to discriminate the patients with mild NPDR who will later develop STDR. An individual prospective cohort with a follow-up period of 3 years was used for the external validation. In both training and testing sets, involving 306 patients with T2DM, median levels of plasma adiponectin (APN), leptin, and fatty acid-binding protein 4 (FABP4) were significantly higher in the STDR group than those in mild NPDR. Except for adipsin, the other three adipokines, FABP4, APN, and leptin, were selected by PCA and integrated into SVM. The accuracy of the multivariate SVM classification model was acceptable in both the training set (AUC = 0.81, sensitivity = 71%, and specificity = 91%) and the testing set (AUC = 0.77, sensitivity = 61%, and specificity = 92%). 110 T2DM patients with mild NPDR, the high-risk population of STDR, were enrolled for external validation. Based on the SVM, the risk of each patient was calculated. More STDR occurred in the high-risk group than in the low-risk group, which were grouped by the median value of APN, FABP4, and leptin, respectively. The model was validated in an individual cohort using SVM with the AUC, sensitivity, and specificity reaching 0.77, 64%, and 91%, respectively. Adiponectin, leptin, and FABP4 were demonstrated to be associated with the severity of DR and maybe good predictors for STDR, suggesting that adipokines may play an important role in the pathophysiology of DR development.

The role of adiposity, adipokines and polymorphisms of leptin and adiponectin in myelodysplastic syndromes.

The aim of the present study was to investigate the relationship between leptin and adiponectin gene polymorphisms, circulating levels of leptin and adiponectin, adiposity and clinical markers in patients with myelodysplastic syndrome (MDS). This cross-sectional study was conducted with 102 adults and elderly MDS patients and 102 age- and sex-matched controls. Clinical characteristics, co-morbidities, anthropometric data, laboratory evaluation and genetic analysis (polymorphisms -2548G > A/rs7799039 of the LEP gene and +276G > T/rs1501299 of the ADIPOQ gene) were investigated. Serum leptin was higher and adiponectin lower in MDS when compared with controls. There was a significant positive correlation between serum leptin levels and BMI (r = 0·264, P = 0·025), waist circumference (r = 0·235, P = 0·047), body fat percentage (BF %) (r = 0·373, P = 0·001) and the fat mass index (FMI) (r = 0·371, P < 0·001). A lower mean adiponectin was found among patients with high BF %, higher visceral adiposity index and metabolic syndrome. A significant association was found between the AA genotype (mutant) of the LEP polymorphism rs7799039 and male sex and blast excess (≥ 5 %). In addition, a significant association was observed between the TT genotype (mutant) of the ADIPOQ rs1501299 polymorphism and Fe overload. These results demonstrate the importance of a comprehensive and systematic evaluation in patients with MDS in order to identify and control negative factors not related to the disease at an early stage.

Correlation analysis of obesity phenotypes with leptin and adiponectin

Obesity can be categorized as metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). However, individuals with MHO are characterized by the absence of metabolic syndrome (MS) and appear to have lower inflammation levels compared to MUO. This study aimed to investigate the association of obesity phenotypes with leptin (LEP) and adiponectin (ADP). According to the inclusion and exclusion criteria, we selected 178 subjects from the previous cross-sectional survey. Based on the body mass index (BMI) and diagnostic criteria of MS, we divided the individuals into three groups, including healthy control group (HC group), metabolically healthy obesity group (MHO group) and metabolically unhealthy obesity group (MUO group). The concentrations of LEP and ADP in serum were measured, and the association of these two cytokines with different obesity phenotypes were subsequently analyzed. Compared to both the HC and MHO groups, the MUO group showed significantly higher BMI, waist circumference (WC), waist-hip ratio (WHR), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), homeostasis model assessment of insulin resistance (Homa-IR) and blood pressure (P < 0.05). In contrast, serum high-density lipoprotein cholesterol (HDL-C) was notably lower in the MUO group (P < 0.05). ADP was found to have a positive correlation with systolic blood pressure (SBP) and a negative correlation with FPG in the MHO group. In the MUO group, LEP demonstrated a positive correlation with fasting insulin (FINS) and Homa-IR, while ADP showed a positive correlation with TC and SBP. Linear regression analysis further indicated that SBP (β = 0.234, P = 0.043), TG (β = − 0.292, P = 0.001) and LDL-C (β = 0.626, P = 0.000) were independently correlated with ADP, and BMI (β = 0.398, P = 0.002) was independently correlated with LEP in obese individuals. In conclusion, ADP and LEP were closely related with glucose and lipid metabolism in obese individuals, these two cytokines might play critical roles in obesity-associated metabolic disorders.

Rare Variants of Obesity-Associated Genes in Young Adults with Abdominal Obesity.

The increase in the prevalence of overweight, obesity and associated diseases is a serious problem. The aim of the study was to identify rare variants in obesity-associated genes in young adults with abdominal obesity in our population and to analyze information about these variants in other populations. Targeted high-throughput sequencing of obesity-associated genes was performed (203 young adults with an abdominal obesity phenotype). In our study, all of the 203 young adults with abdominal obesity had some rare variant in the genes associated with obesity. The widest range of rare and common variants was presented in ADIPOQ, FTO, GLP1R, GHRL, and INS genes. The use of targeted sequencing and clinical criteria makes it possible to identify carriers of rare clinically significant variants in a wide range of obesity-associated genes and to investigate their influence on phenotypic manifestations of abdominal obesity.

Evaluation of the correlation between fetuin-B levels and essential hypertension: a cross-sectional study.

Fetuin-B, a cytokine that regulates lipid metabolism, has recently been linked to cardiovascular diseases such as coronary heart disease. In this study, we discussed the relationship between fetuin-B and essential hypertension. A bioinformatics analysis of fetuin-B was performed. A total of 206 with essential hypertension and 180 age- and-sex-matched healthy subjects were enrolled. Plasma fetuin-B, endothelin 1 (ET-1), nitric oxide (NO), and adiponectin (ADI) levels were measured using ELISA kits. Bioinformatics analysis has revealed that fetuin-B plays an important role in pathways such as lipid metabolism. Compared with healthy subjects, serum fetuin-B levels in patients with essential hypertension were significantly increased. Correlation analysis showed that the serum fetuin-B level was positively correlated with systolic blood pressure (SBP), diastolic blood pressure, body mass index, fat percentage in vivo, waist-hip ratio, intima-media thickness, low-density lipoprotein cholesterol (LDL-C), glutamyltranspeptidase, alanine transaminase, albumin, fasting blood glucose (FBG), glycated hemoglobin, and ET-1 in the overall study subjects (all P < 0.05) and negatively correlated with HDL-C, ADI, and NO (all P < 0.05). Multivariate linear regression analysis showed that SBP, FBG, LDL-C, ADI, and ET-1 were independent factors affecting serum fetuin-B. A binary logistic regression analysis showed that fetuin-B was an independent risk factor for primary hypertension (odds ratio: 1.060, 95% CI: 1.034-1.086, P < 0.001). Receiver operating characteristic curve analysis was used to evaluate the predictive value of fetuin-B for primary hypertension, and the optimal cutoff point was 83.14 μg/mL (sensitivity 77.4%, specificity 63.3%) (area under the curve) = 0.7738, 95% CI 0.7276-0.8200, P < 0.001). Elevated fetuin-B levels are associated with an increased risk of essential hypertension.

Dysfunctional APPL1-Mediated Epigenetic Regulation in Diabetic Vascular Injury.

APN (adiponectin) and APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) are potent vasculoprotective molecules, and their deficiency (eg, hypoadiponectinemia) contributes to diabetic vascular complications. However, the molecular mechanisms that govern their vasculoprotective genes as well as their alteration by diabetes remain unknown. Diabetic medium-cultured rat aortic endothelial cells, mouse aortic endothelial cells from high-fat-diet animals, and diabetic human aortic endothelial cells were used for molecular/cellular investigations. The in vivo concept-prove demonstration was conducted using diabetic vascular injury and diabetic hindlimb ischemia models. In vivo animal experiments showed that APN replenishment caused APPL1 nuclear translocation, resulting in an interaction with HDAC (histone deacetylase) 2, which inhibited HDAC2 activity and increased H3Kac27 levels. Based on transcriptionome pathway-specific real-time polymerase chain reaction profiling and bioinformatics analysis, Angpt1 (angiopoietin 1), Ocln (occludin), and Cav1 (caveolin 1) were found to be the top 3 vasculoprotective genes suppressed by diabetes and rescued by APN in an APPL1-dependent manner. APN reverses diabetes-induced inhibition of Cav1 interaction with APPL1. APN-induced Cav1 expression was not affected by Angpt1 or Ocln deficiency, whereas APN-induced APPL1 nuclear translocation or upregulation of Angpt1/Ocln expression was abolished in the absence of Cav1 both in vivo and in vitro, suggesting Cav1 is upstream molecule of Angpt1/Ocln in response to APN administration. Chromatin immunoprecipitation-qPCR (quantitative polymerase chain reaction) demonstrated that APN caused significant enrichment of H3K27ac in Angpt1 and Ocln promoter region, an effect blocked by APPL1/Cav1 knockdown or HDAC2 overexpression. The protective effects of APN on the vascular system were attenuated by overexpression of HDAC2 and abolished by knocking out APPL1 or Cav1. The double knockdown of ANGPT1/OCLN blunted APN vascular protection both in vitro and in vivo. Furthermore, in diabetic human endothelial cells, HDAC2 activity is increased, H3 acetylation is decreased, and ANGPT1/OCLN expression is reduced, suggesting that the findings have important translational implications. Hypoadiponectinemia and dysregulation of APPL1-mediated epigenetic regulation are novel mechanisms leading to diabetes-induced suppression of vasculoprotective gene expression. Diabetes-induced pathological vascular remodeling may be prevented by interventions promoting APPL1 nuclear translocation and inhibiting HDAC2.

SAT091 Genetic Investigation Of The Susceptibility To Develop Type 1 Diabetes And Diabetic Nephropathy

Abstract Disclosure: I. Brema: None. A. Aljuryyan: None. B. Bradley: None. A.E. Osman: None. Diabetic Nephropathy (DN) is one of the leading causes of end-stage renal disease (ESRD) worldwide and is a major cause of morbidity and mortality in subjects with type 1 diabetes (T1DM). Several single nucleotide polymorphisms (SNP) have been found in various gene variants such as the ACE, NOS 3, and FRMD 3 genes that play a major role in genetic susceptibility to DN, however, there is lack of wide replication of these studies, particularly in non-Caucasian ethnic groups. Therefore, the aim of this study was to identify SNPs that increase the susceptibility to develop T1DM as well as microalbuminuria (the hallmark of DN) in a Saudi cohort of subjects with T1DM. We conducted a case-control study in 179 subjects with T1DM and 180 healthy normal controls comparing genotype frequency of 11 SNPs that have been shown to increase the susceptibility to develop DN in subjects with T1DM, namely, rs1799983, rs2070744 (NOS3 gene); rs560807, rs 1059982 (CAT gene), rs1888747, rs10868025, rs361525, rs1800629 (FRMD3 gene), rs182052, rs 17300539 (ADIPOQ gene) and rs1799752(ACE gene). We report that the A/G rs361525 (FRMD3) genotype has significantly higher frequency in controls compared to subjects with T1DM (9 % vs 0), p value 0.01) and it seems to be protective against the risk of T1DM development. Moreover, the A/A rs17300539 (ADIPOQ gene) genotype has significant higher frequency in controls compared to subjects with T1DM (7 % vs 0.5), p value 0.02) and seems to be protective against type 1 development as well. We did not detect any further associations between the remaining 9 genotype SNPs and the risk of T1DM. On the other hand, we report no association between all the 11 studied SNPs referenced above and the risk of developing diabetic nephropathy. We have studied several DN susceptibility SNPs that have been shown to increase the risk of albuminuria and ESRD development in Caucasians with T1DM , however, we were unable to replicate previous findings in this Saudi cohort of patients with T1DM. Future larger multicenter studies are needed in larger numbers of patients to replicate the findings of the studies that were done in Caucasians and other ethnic groups, ideally Genome-wide association studies. Presentation: Saturday, June 17, 2023