Secreted Frizzled-related Protein 5 Levels Research Articles

Secreted frizzled-related protein 5: A promising therapeutic target for metabolic diseases via regulation of Wnt signaling

Metabolic diseases pose a significant global health challenge, characterized by an imbalance in metabolism and resulting in various complications. Secreted frizzled-related protein 5 (SFRP5), an adipokine known for its anti-inflammatory properties, has gained attention as a promising therapeutic target for metabolic diseases. SFRP5 acts as a key regulator in the Wnt signaling pathway, exerting its influence on critical cellular functions including proliferation, differentiation, and migration. Its significance extends to the realm of adipose tissue biology, where it plays a central role in regulating inflammation, insulin resistance, adipogenesis, lipid metabolism, glucose homeostasis, and energy balance. By inhibiting Wnt signaling, SFRP5 facilitates adipocyte growth, promotes lipid accumulation, and contributes to a decrease in oxidative metabolism. Lifestyle interventions and pharmacological treatments have shown promise in increasing SFRP5 levels and protecting against metabolic abnormalities. SFRP5 is a pivotal player in metabolic diseases and presents itself as a promising therapeutic target. An overview of SFRP5 and its involvement in metabolic disorders and metabolism is provided in this comprehensive review. By elucidating these aspects, valuable insights can be gained to foster the development of effective strategies in combating metabolic diseases.

Association of Circulating Plasma Secreted Frizzled-Related Protein 5 (Sfrp5) Levels with Cardiac Function.

Secreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine that may play a role in cardiovascular development and disease. However, there is yet to be a comprehensive investigation into whether circulating SFRP5 can be a biomarker for cardiac function. Plasma SFRP5 levels were measured via ELISA in 262 patients admitted to a cardiology unit. Plasma SFRP5 levels were significantly lower in patients with a history of heart failure (HF), coronary artery disease (CAD), and atrial fibrillation (AF; p = 0.001). In univariate analyses, SFRP5 levels were also significantly positively correlated with left ventricular ejection fraction (LVEF) (r = 0.52, p < 0.001) and negatively correlated with E/E' (r = -0.30, p < 0.001). Patients with HF, CAD, low LVEF, low triglycerides, high CRP, and high eGFR were associated with lower SFRP5 levels independent of age, BMI, or diabetes after multivariate analysis (overall model r = 0.729, SE = 0.638). Our results show that low plasma SFRP5 levels are independently associated with the presence of HF, CAD, and, importantly, impaired LV function. These results suggest a potential role of SFRP5 as a biomarker, as well as a mediator of cardiac dysfunction independent of obesity and metabolic regulation.

A Study to Evaluate the Role of Secreted Frizzled-Related Protein 4 (SFRP4) as a Potential Novel Biomarker of Type 2 Diabetes Mellitus

ABSTRACT Background: A new inflammation mediator called secreted frizzled-related protein 4 (SFRP4), was recently found, the secretion of which is regulated by interleukin-1β. SFRP4 as a potential biomarker of early β-cell dysfunction can help to identify high-risk individuals who are going to develop diabetes in the future. It is highly expressed in β-cells of islets and its levels increase several years before diabetes diagnosis. Objectives: This study was conducted with an objective to estimate and correlate SFRP4 in pre-diabetes, type 2 diabetes, and non-diabetes persons, and evaluate the predictive risk assessment of SFRP4 as a novel biomarker. Materials and Methods: In this cross-sectional observational study, a total of 300 human participants were included among which 100 were prediabetic, 100 were diabetic, and 100 were age- and gender-matched control individuals from a community, all of whom were selected through a predesigned screening questionnaire and inclusion and exclusion criteria from January 2020 to January 2022 in Banke district, Nepal. Serum SFRP4 and IL-1β levels were determined by ELISA. Results: There was a statistically significant difference in body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), fasting insulin, fasting plasma glucose (FPG), two-hour post-load plasma glucose (2hPG), glycosylated hemoglobin (HbA1c), insulin resistance (HOMA-IR), Homeostasis model assessment of β cell function (HOMA-β%), high-sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) between the three groups, with a progressive increase from the normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) groups and with the highest value in the type 2 diabetes mellitus (T2DM) groups (P &lt; 0.05). However, diastolic blood pressure (DBP) and IL-1β showed a significant difference between the NGT and T2DM groups (P &lt; 0.001) and the NGT and IGT groups (P &lt; 0.001). The median serum SFRP4 concentrations showed a significant difference among three groups (all P &lt; 0.05) and were positively correlated with FPG, HbA1c, hs-CRP, and IL-1 β (P &lt; 0.05). Conclusion: Our study presumes importance as we report increased SFRP4 levels in Asian Nepalis even at the stage of IGT. These findings propose that the increased serum SFRP4 may be a good biomarker of decline in β-cell function and insulin resistance.

Secreted Frizzled Related Protein 5 (SFRP5) Serum Levels Are Decreased in Critical Illness and Sepsis and Are Associated with Short-Term Mortality

Sepsis is a major health burden with insufficiently understood mechanisms of inflammation and immune paralysis, leading to a life-threatening critical illness. The secreted frizzled related protein 5 (SFRP5) acts as an anti-inflammatory adipokine by antagonizing the Wnt5a pathway. The aim of this study was to elucidate the role of SFRP5 in critical illness and sepsis and to determine its value as a prognostic biomarker for mortality. We analyzed SFRP5 serum concentrations of 223 critically ill patients at admission to a medical intensive care unit (ICU) and compared those to 24 healthy individuals. SFRP5 serum concentrations were significantly decreased in critical illness as compared to healthy controls (24.66 vs. 100 ng/mL, p = 0.029). Even lower serum concentrations were found in septic as compared to nonseptic critically ill patients (19.21 vs. 32.83 ng/mL, p = 0.031). SFRP5 concentrations correlated with liver disease, age, anti-inflammation, and metabolic parameters. Furthermore, patients with sepsis recovered levels of SFRP5 in the first week of ICU treatment. SFRP5 levels at admission predicted short-term mortality in critically ill but not in septic patients. This study points to the role of the anti-inflammatory mediator SFRP5 not only in sepsis but also in nonseptic critically ill patients and associates high levels of SFRP5 to worse outcomes, predominantly in nonseptic critically ill patients.

Heart failure is associated with low circulating levels of secreted frizzled receptor protein 5 (Sfrp5)

Abstract Background/Introduction Obesity and metabolic dysregulation are closely associated with the pathophysiology of multiple cardiovascular diseases (CVD). To date, the pathophysiological mechanism(s) of obesity and its link with cardiovascular systems remain largely unknown. Adipose tissue inflammation as a result of excessive fat expansion in obesity, leading to increased systemic production of growth factors and recruitment of inflammatory cells have been postulated to be a major factor. Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that is linked with obesity and metabolic regulation and has been indicated to affect cardiovascular functions. Currently, the role of circulating SFRP5 levels as a biomarker for cardiovascular diseases are poorly understood, with studies yielding discordant results. Purpose This study aims to evaluate the relationship between circulating SFRP5 and cardiovascular functions in a cohort of patients with established CVD. Methods Patients (n=262, 148 male (56.5%), age (68±11 yrs)) presenting to the cardiology unit for cardiovascular investigations were recruited into the study. Plasma SFRP5 levels were measured via enzyme-linked immunosorbent assay (ELISA). Associations between plasma SFRP5 levels, cardiovascular functions, and patients' co-morbidities were analysed using univariate and multivariate analyses. Results Plasma SFRP5 levels were significantly lower in patients presenting with: heart failure (HF) vs non-HF (median; (10.7 vs 31.0; p&amp;lt;0.001); coronary artery disease (CAD) vs non-CAD; (11.0 vs 33.8; p&amp;lt;0.001); and atrial fibrillation (AF) vs non-AF; (11.2 vs 23.2; p=0.001). On univariate analyses, SFRP5 levels also significantly positively correlated with left ventricular ejection fraction (LVEF) (r=0.52, p&amp;lt;0.001), estimated glomerular filtration rate (eGFR) (r=0.16, p=0.02), total cholesterol levels and triglycerides (r=0.29, p&amp;lt;0.001; r=0.17, p&amp;lt;0.01 respectively). Low SFRP5 levels were correlated with high C-reactive protein (CRP) and E/E' (r=−0.29, p&amp;lt;0.001, r=−0.30, p&amp;lt;0.001, respectively). Patients with HF, CAD, statin use, low LVEF, low triglycerides, high CRP and high eGFR were associated with lower SFRP5 levels independent of age, BMI or diabetes on multivariate analysis (overall model r=0.729, SE=0.638). Conclusion Our results show that low plasma SFRP5 levels are independently associated with HF, CAD, and impaired systolic and diastolic functions. These results suggest that SFRP5 may regulate cardiovascular functions independent of obesity and metabolic regulations. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Heart Foundation of Australia Future Leader FellowshipsNSW Ministry of Health EMC FellowshipHeart Foundation of Australia Future Leader Fellowship

Effects of Dapagliflozin in Combination with Metoprolol Sustained-Release Tablets on Prognosis and Cardiac Function in Patients with Acute Myocardial Infarction after PCI.

Objective To find the effects of dapagliflozin in combination with metoprolol sustained-release tablets on cardiac function and prognosis in acute myocardial infarction patients after PCI. Methods A total of 84 patients with myocardial infarction who experienced PCI from February 2020 to February 2022 were included and allocated into 3 groups: groups A, B, and C (n = 28/per group). Group A was given dapagliflozin combined with metoprolol sustained-release tablets, group B was given dapagliflozin, and group C was given the placebo. Left ventricular end diastolic diameter (EDD), left ventricular ejection fraction (LVEF), and end systolic diameter (ESD) were measured before and after treatment in all groups; myocardial infarction areas were matched among all three groups at 3 months posttreatment. The serum concentrations of interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), superoxide dismutase (SOD), and malondialdehyde (MDA) were detected in all three groups before and after treatment. The levels of N-terminal probrain natriuretic peptide (NT-pro BNP), lipoprotein (a) (Lp(a)), ischemia-modified albumin (IMA), and secreted frizzled-related protein 5 (SFRP5) were also detected in the serum of all groups. Adverse reactions and cardiovascular adverse events were matched between all groups. Results The levels of LVEF in groups A and B were increased after treatment, while the levels of EDD and ESD were decreased. The improvement degree of LVEF and EDD levels in groups A and B was found greater compared to group C (P < 0.05). No significant difference was found in myocardial infarction area among the three groups at 3 months postoperation (P > 0.05). Serum concentrations of MDA, hs-CRP, IL-6, IMA, NT-proBNP, and Lp(a) were found to decrease in all three groups after treatment, while the levels of SOD and SFRP5 were increased. The improvement degree of serum hs-CRP, IL-6, SOD, MDA, IMA, NT-proBNP, Lp(a), and SFRP5 levels was greater in both groups A and B compared to group C. The improvement degree of serum hS-CRP, SOD, MDA, IMA, Nt-probNP, Lp(a), and SFRP5 levels was significantly greater in group A compared to group B (P < 0.05). No adverse effect was observed in all three groups (P > 0.05). Total occurrence of cardiovascular adverse effects such as stent thrombosis, heart failure, ventricular fibrillation, and death was 10.71% in group A, 25.00% in group B, and 53.75% in group C. There was statistical significance in the onset of cardiovascular adverse effects 3 months postoperation among all three groups (P < 0.05). Conclusion Dapagliflozin with metoprolol sustained-release tablets can be effective in improving the heart function, inflammatory response, oxidative stress response, and prognosis in patients after PCI.

PPARγ attenuates hepatic inflammation and oxidative stress of non‑alcoholic steatohepatitis via modulating the miR‑21‑5p/SFRP5 pathway.

Inflammation and oxidative stress are key steps in the progression of non-alcoholic steatohepatitis (NASH). Intervention in these two processes will therefore benefit NASH treatment. Peroxisome proliferator-activated receptor γ (PPARγ), as a multiple functional transcription factor, has been reported to be involved in the prevention of NASH progression. However, the mechanism by which PPARγ prevents NASH remains to be elucidated. The present study demonstrated that the level of PPARγ was inversely correlated with that of microRNA (miRNA/miRs)-21-5p in both mice and humans with NASH. Activation of PPARγ inhibited lipid droplet accumulation, hepatic inflammation and oxidative stress by downregulating miR-21-5p in an in vitro model. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that PPARγ suppressed transcriptional activity of miR-21-5p and bound to miR-21-5p promoter region. Furthermore, PPARγ downregulated miR-21-5p while miR-21-5p upregulated secreted frizzled-related protein 5 (SFRP5) by targeting the 3′-UTR of its mRNA. In vivo experiments revealed that PPARγ repressed inflammation and oxidative stress and miR-21-5p expression while increased SFRP5 level in a NASH mouse model. In summary, PPARγ attenuates inflammation and oxidative stress in NASH by modulating the miR-21-5p/SFRP5 pathway, thus holding promise of a new target for NASH treatment.

Deregulation of Secreted Frizzled-Related Protein 5 in Nonalcoholic Fatty Liver Disease Associated with Obesity

Secreted frizzled-related protein 5 (SFRP5), an antagonist of the noncanonical WNT pathway, has a controversial role in liver disease. The aim of this study was to analyze the role of SFRP5 and the noncanonical WNT pathway in nonalcoholic fatty liver disease (NAFLD). Plasma SFRP5 levels were determined by ELISA in women with normal weight (NW; n = 20) and morbid obesity (MO; n = 69). Women with MO were subclassified according to hepatic histology into normal liver (NL; n = 28), NAFLD (n = 41) (simple steatosis (SS; n = 24), and nonalcoholic steatohepatitis (NASH; n = 17)). We used RT-qPCR to evaluate the hepatic mRNA expression of SFRP5, WNT5A, and JNK in women with MO. SFRP5 levels were lower in NW than in MO patients who underwent a very low-calorie diet before surgery. Hepatic SFRP5 mRNA expression was higher in SS than in NL or NASH; additionally, patients with hepatic inflammation or ballooning presented lower SFRP5 abundance. WNT5A and JNK expression was enhanced in NAFLD compared with NL. In conclusion, circulating SFRP5 levels depend on the diet, and hepatic SFRP5 seems to have a protective role in the first steps of NAFLD; however, SFRP5 could be deregulated in an advanced stage while WNT5A and JNK are activated, promoting liver damage.

Secreted Frizzled-Related Protein 5 is Associated with Glucose and Lipid Metabolism Related Metabolic Syndrome Components Among Adolescents in Northeastern China.

PurposeSecreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine that has been associated with various metabolic diseases. However, such relationship among adolescents remains unclear. The purpose of this study was to clarify the relationship between SFRP5 and the components of metabolic syndrome in Chinese adolescents.Patients and MethodsIn this cross-sectional study, we included a total of 684 adolescents aged 11–16 years old from Liaoyang city, Liaoning province, China. The ELISA kits were implemented to measure the plasma SFRP5 and high-sensitivity C-reactive protein. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), serum uric acid (UA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting plasma glucose (FPG), and fasting serum insulin (FINS) were also measured.ResultsThe multivariate logistic regression analysis showed that low SFRP5 level were an independent risk factor of high FPG [odds ratio (OR)=5.31, 95% confidence interval (CI): 1.85–15.22, P<0.01] and high TC (OR=1.73, 95% CI: 1.01-2.96, P<0.05) when adjusting for age, sex, family history of diabetes, body mass index, and high-sensitivity C-reactive protein.ConclusionThe lower level of SFRP5 is strongly related to lipid and glucose metabolism among adolescents in Northeast China. The risk of high fasting plasma glucose and high total cholesterol increases significantly as the plasma SFRP5 level decreases.

The regulatory role of SFRP5/WNT5A axis in allergic rhinitis through inhibiting JNK pathway activation and lowering mucin generation in human nasal epithelial cells

Allergic rhinitis (AR) is tightly associated with type 2 inflammation. SFRP5 combined with WNT5A mainly inhibits chronic inflammatory response, atherosclerosis, and other metabolic disorders. However, the effect of SFRP5/WNT5A axis on recombinant human interleukin-13 (rhIL-13)-induced inflammation has not been studied. In this study, we aimed to investigate whether secreted frizzled-related protein 5 (SFRP5) could modulate the production of cytokines relevant to eosinophil infiltration and mucin secretion through blocking the activation of Wnt family 5A (WNT5A) signaling pathway. A mouse model of AR demonstrated low expression of SFRP5 and high expression of WNT5A, and indicated that the number of eosinophil and goblet cells was increased, concomitant with elevated IL-13, colony stimulating factor 2 (CSF2), chemokine ligand 11 (CCL11), Mucin 4, and Mucin 5AC levels. Furthermore, lentivirus-SFRP5 overexpression up-regulated the expression of SFRP5 but down-regulated WNT5A level, and inhibited the activation of JNK pathway via decreasing p-JNK1/2 (Thr183/Tyr185) and p-c-Jun (Ser73) protein expressions in rhIL-13-treated human nasal epithelial cells (HNEpCs). Noticeably, SFRP5 overexpression markedly reduced rhIL-13-induced inflammatory protein and mucin generation through lowered CSF2, CCL11, Mucin 4, as well as Mucin 5AC levels. Taken together, these findings confirmed the regulatory role of SFRP5/WNT5A axis in rhIL-13-mediated inflammatory response in HNEpCs.

Prognostic Value of Secreted Frizzled-Related Protein 5 in Heart Failure Patients With and Without Type 2 Diabetes Mellitus.

Patients with heart failure (HF) with diabetes mellitus have distinct biomarker profiles compared with those without diabetes mellitus. SFRP5 (secreted frizzled-related protein 5) is an anti-inflammatory adipokine with an important suppressing role on the development of type 2 diabetes mellitus (T2DM). This study aimed to evaluate the prognostic value of SFRP5 in patients with HF with and without T2DM. The study included 833 consecutive patients with HF, 312 (37.5%) of whom had T2DM. Blood samples were collected at presentation, and SFRP5 levels were measured. The primary outcome was the composite end points of first occurrence of HF rehospitalization or all-cause mortality during follow-up. During median follow-up of 2.1 years, 335 (40.2%) patients in the cohort experienced the composite primary outcome. After adjustment for multiple risk factors, each doubling of SFRP5 level was associated with a 21% decreased risk of primary outcomes in the overall study population (P<0.001). Subgroup analyses showed that the association between level of SFPR5 and primary outcomes may be stronger in patients with T2DM (hazard ratio, 0.69 [95% CI, 0.61-0.79]) than in patients without T2DM (hazard ratio, 0.89 [95% CI, 0.79-1.01]; interaction P=0.006). Similar associations were observed when taking SFRP5 as a categorical variable. Addition of SFRP5 significantly improved discrimination and reclassification of the incident primary outcomes beyond clinical risk factors and N-terminal pro-B-type natriuretic peptide in all patients with HF and those with T2DM (all P<0.01). SFRP5 is an independent novel biomarker for risk stratification in HF, especially in HF with T2DM.

Correlation Between Circulating Levels of Secreted Frizzled-Related Protein 5 and Type 2 Diabetic Patients and Subjects with Impaired-Glucose Regulation.

BackgroundSecreted frizzled-related protein 5 (SFRP5) is a recently identified adipokine; however, its functions during pathogenesis of T2DM and obesity remain unclear. This research attempted to investigate associations between circulating SFRP5 and obesity/T2DM.Materials and MethodsAccording to diagnosis, 107 patients were assigned as impaired-glucose regulation (IGR) and 111 patients newly-diagnosed as T2DM were assigned as the T2DM group. Meanwhile, 132 subjects with normal-glucose tolerance (NGT) were assigned as the NGT group. Differences in plasma SFRP5 levels among three groups were compared. Correlation between SFRP5 levels and different metabolic markers was analyzed. Multiple-linear stepwise regression analyses were performed to determine independent factors for SFRP5. Patients in the T2DM group were administrated with metformin for 12 weeks. Meanwhile, changes in plasma SFRP5 levels were also analyzed.ResultsPlasma SFRP5 level of the IGR group was significantly lower compared to the NGT group (219.1±39.7 pg/mL vs 236.7±72.6 pg/mL, P<0.05), however, that of the T2DM group was significantly lower compared to the IGR group (203.5±42.1 pg/mL vs 219.1±39.7 pg/mL, P<0.01). Level of plasma SFRP5 was negatively correlated with fasting plasma glucose, BMI, waist circumference (WC), normalized WC (waist-to-height ratio) (WHtR), 2h plasma glucose, fasting insulin, glycosylated hemoglobin (HbA1c), fasting C-peptide, HOMA-IR, and hs-CRP (P<0.01). Among the above factors, HbA1c and fasting insulin levels (FIns) were two independent factors. Plasma SFRP5 levels were increased after 12-week metformin treatment (201.0±34.8 pg/mL vs 213.1±34.4 pg/mL, P<0.05), while insulin resistance was alleviated (ln(HOMA-IR): 1.35±0.55 vs 1.07±0.49, P<0.01).ConclusionMetformin reduced circulating levels of secreted frizzled-related protein 5 and improved pathophysiological parameters of T2DM.

Adipocyte-derived SFRP5 inhibits breast cancer cells migration and invasion through Wnt and epithelial-mesenchymal transition signaling pathways.

ObjectiveObesity is closely associated with metastasis in breast cancer patients. Secreted frizzled-related protein 5 (SFRP5), one of the novel adipokines with anti-inflammatory properties, is associated with obesity. This study aims to study the role of SFRP5 in the crosstalk between obesity and breast cancer metastasis and identify the underlying mechanism.Methods3T3-L1 pre-adipocytes were differentiated to mature adipocytes and a hypertrophic adipocyte model was induced with palmitic acid (PA). Cell motility was measured in MDA-MB-231 and MCF-7 breast cancer cells co-cultured with adipocytes conditioned medium (CM) with or without SFRP5 protein. Wnt and epithelial-mesenchymal transition (EMT) signal pathways were investigated by western blot. Circulating SFRP5 level in 218 breast cancer patients and the association with clinicopathologic characteristics of breast cancer were further determined. Online databases ENCORI and PREDICT Plus were used to exam the link between SFRP5 and prognosis.ResultsReduced SFRP5 level was detected in the hypertrophic adipocyte model. Recombinant SFRP5 protein inhibited MDA-MB-231 and MCF-7 cells invasion and migration induced by PA-treated adipocyte CM, and SFRP5 inhibition by specific antibody reversed the effect of SFRP5. Furthermore, SFRP5 significantly inhibited Wnt and downstream EMT in breast cancer cells. Low circulating SFRP5 level correlated with body mass index (BMI), lymph node (LN) metastasis, TNM stage and high Ki67 expression in breast cancer patients. Increased SFRP5 level was associated with favorable predicted survival. Kaplan-Meier curves showed high SFRP5 level in tumor tissue was associated with better outcome of breast cancer patients.ConclusionsOur findings demonstrated SFRP5 is a vital adipokine that mediates the crosslink between obesity and the metastatic potential of breast cancer. Promotion of SFRP5 expression in the adipose microenvironment may represent a novel approach for preventing breast cancer metastasis.

Elevated circulating levels of secreted frizzled-related protein 4 in relation to insulin resistance and androgens in women with polycystic ovary syndrome.

Secreted frizzled-related protein 4 (SFRP4) is an adipokine involving in apoptotic process during ovulation and energy metabolism. Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder associated with insulin resistance and impaired oocyte maturation as well as apoptotic dysfunctions through oocyte development. Our aim was to determine whether there was an alteration in levels of SFRP4 and if there was an association between metabolic or hormonal parameters and SFRP4 in women with PCOS. We enrolled 80 subjects with PCOS and 80age- and body mass index (BMI)-matched subjects with normal menstrual cycle into current case-control study. Metabolic and hormonal parameters of enrolled subjects were determined. Circulating SFRP4 levels were measured with ELISA method. We found that circulating SFRP4 levels were elevated in women with PCOS with respect to controls (5.87 ± 1.91 vs. 3.72 ± 1.29ng/ml, P < 0.001). We also found a positive association between SFRP4 and insulin resistance, androgens, ovarian follicular number or ovarian volume in women with PCOS. Binary logistic regression analysis revealed that subjects with the highest tertile of SFPR4 levels displayed increased possibility of having PCOS risk compared to those subjects with the lowest tertile of SFRP4 levels. Increased SFRP4 levels were not only associated with higher possibility of having PCOS but also related to insulin resistance, hyperandrogenism, ovarian follicular number and ovarian volume, suggesting that SFPR4 could be a player in different pathophysiologic pathways of PCOS.

Cinnamon extract combined with high-intensity endurance training alleviates metabolic syndrome via non-canonical WNT signaling.

The incidence of metabolic syndrome (MetS) in menopausal women is one of the main health care concerns. MetS clusters are related to an imbalance in pro- and anti-inflammatory adipokines such as secreted frizzled-related protein 5 (SFRP5) and wingless-type mammary tumor virus integration site family, member 5A (WNT5A). WNT5A induces an inflammatory state to induce insulin resistance and further pathologic consequences. Recent strategies to prevent progression of MetS to diabetes have focused on conservative treatments such as exercise and herbal medicine. The aim of this study was to investigate the mechanistic effects of cotreatment with cinnamon extract and 12-wk high-intensity endurance training on MetS components considering the non-canonical WNT5A signaling. Thirty-two female ovariectomized Wistar rats were divided into the following four groups (n = 8/group): exercise (Ova+Exe), cinnamon extract (Ova+Cin), exercise with cinnamon extract (Ova+Exe+Cin) and saline (Ova+Sal). One group of rats undergoing surgery without removal of the ovaries was considered as a sham. After 3 mo of experimental intervention, waist circumference, serum concentrations of glucose, insulin, lipid profile, tumor necrosis factor-α, WNT5A, and SFRP5 were measured. Data showed a significant reduction in serum glucose, low-density lipoprotein, homeostasis model assessment estimate of insulin resistance, and tumor necrosis factor-α, but an increase in SFRP5 level in Ova+Exe, Ova+Cin and Ova +Exe+Cin groups compared with Ova+Sal group (P < 0.05). Serum WNT5A significantly was reduced only in Ova+Exe+Cin group (P = 0.02). The present study indicated that high-endurance training combined with aqueous cinnamon extract supplementation for 12 wk more efficiently alleviated insulin resistance and metabolic dysfunctions via reduction in noncanonical WNT signaling in ovariectomized rats.

Umbilical Cord SFRP5 Levels of Term Newborns in Relation to Normal and Excessive Gestational Weight Gain.

Among the new adipokines, secreted frizzled-related protein 5 (SFRP5) is considered to prevent obesity and insulin resistance. The umbilical cord SFRP5 levels have not yet been investigated. The main aim of the study was to investigate whether the umbilical cord SFRP5 concentrations are altered in term neonates born to mothers with excessive gestational weight gain (EGWG). Two groups of subjects were selected depending on their gestational weight gain, i.e. 28 controls and 38 patients with EGWG. Umbilical cord and maternal serum SFRP5 levels were lower in the EGWG group. Umbilical cord SFRP5 concentrations were directly associated with the maternal serum SFRP5, hemoglobin A1c and lean tissue index, umbilical cord leptin levels, as well as newborns’ anthropometric measurements in the EGWG subjects. In multiple linear regression models performed in all the study participants, umbilical cord SFRP5 concentrations depended positively on the maternal serum SFRP5, ghrelin, and leptin levels and negatively on the umbilical cord ghrelin levels, low-density lipoprotein cholesterol, pre-pregnancy body mass index, and gestational weight gain. EGWG is associated with disturbances in SFRP5 concentrations. Obstetricians and midwives should pay attention to nutrition and weight management during pregnancy.

The relationship between carotid intima-media thickness and serum secreted frizzled-related protein-4 and dipeptidyl peptidase-4 in diabetic patients with cardiovascular diseases.

We investigated the association between carotid intima-media thickness (CIMT) with clusterin (CLU), amylin, secreted frizzled-related protein-4 (SFRP-4), glucagon-like peptide-1 (GLP-1) levels, and dipeptidyl peptidase-4 (DPP-4) in type 2 diabetes mellitus (T2DM) individuals with or without coronary artery disease (CAD). This study consisted of four groups: control group (mean ages: 50.3±10.7 years; 20 females and 15 males), diabetic group (DM; mean ages: 53.9±11.1; 14 females and 23 males), CAD group (mean ages: 60.1±43.5; 17 females and 17 males) and CAD+DM group (mean ages: 62.6±11.8 years; 18 females and 18 males). CIMT levels in both CAD and CAD+DM groups are higher than those in controls. CIMT levels in CAD+DM group are also significantly higher than those in DM group. Left external carotid artery (ECA) was found different from controls only in DM group. The levels of SFRP-4 in control group were significantly lower than those in DM, CAD and CAD+DM groups. Serum GLP-1total levels were found to be significantly low in CAD+DM group when compared to control group. DPP-4 and SFRP-4 levels may be a predictive marker for atherosclerosis in diabetes while particularly in diabetes, they correlate well with HOMA-IR. CIMT has the potential to be a clinically useful predictor of vascular risk in diabetic patients with CAD (Tab. 3, Fig. 2, Ref. 39). Keywords: type 2 diabetes mellitus, carotid intima-media thickness, glucagon-like peptide-1, dipeptidyl peptidase-4, clusterin, amylin, secreted frizzled-related protein-4.

Inverse Associations between Circulating SFRP5 and Adiposity among African-Caribbean Men

Background: African ancestry populations are at the epicenter of the obesity and diabetes epidemic. Secreted frizzled-related protein 5 (SFRP5) is a novel adipokine and Wnt pathway modulator which is thought to be inversely related with adiposity and diabetes risk, however data in humans is conflicting. Therefore, we examined the association of SFRP5 with parameters of obesity and insulin resistance among an African ancestry population. Methods: We measured fasting serum SFRP5 in a pilot study of 139 elderly Afro-Caribbean men (mean age 71.7years, mean BMI 27.6 kg/m2). These men represented a random subset of a population-based study comprising ∼3000 African ancestry men with anthropometrics, DXA measured adiposity, and fasting morning blood collections for biomarker analysis. SFRP5 was measured in duplicate in previously unthawed serum with ELISA. Results: Using Pearson correlations, we found SFRP5 level to be positively associated with age (R = 0.18, p = 0.03) and negatively associated with BMI (R = - 0.14, p = 0.09), waist circumference (R = - 0.18, p = 0.02) and DXA trunk fat (R = - 0.24, p = 0.003), independent of age. Among nondiabetics (N=87), SFRP5 was inversely associated with fasting insulin levels (R = - 0.21, p= 0.04) and to some extent with HOMA-IR (R = -0.20, p = 0.06), independent of age and BMI. However, after adjustment for age and waist circumference, the associations between SFRP5 and fasting serum insulin and HOMA-IR were no longer significant. Conclusion: Our findings suggest that among African ancestry men, SFRP5 might have a beneficial role against general and central obesity. Our findings also suggest that the link between SFRP5 and diabetes risk in African Ancestry men may be explained by its correlation with central adiposity. Additional larger studies among African ancestry populations are needed to explore this novel biomarker along with its temporal relationship with clinically relevant metabolic outcomes. Disclosure H. Ali: None. J.M. Zmuda: None. R. Cvejkus: None. E.E. Kershaw: Consultant; Self; Regeneron Pharmaceuticals, Inc.. A.L. Kuipers: None. C.H. Bunker: None. I. Miljkovic: None.

ASSOCIATION OF ASYMPTOMATIC TARGET ORGAN DAMAGES WITH SECRETED FRIZZLED RELATED PROTEIN 5 IN THE ELDERLY

Objective: Secreted frizzled related protein 5 (SFRP5) is a novel anti-inflammatory adipokine which is implicated in metabolic and cardiovascular disease (CVD). However, little is known about the relevance of SFRP5 with asymptomatic hypertensive target organ damages (TOD). We aimed to investigate the association between SFRP5 and TOD in a large population study.Design and method: Associations between plasma SFRP5 and cardiovascular risk factors as well as TOD were investigated in 1745 participants from Northern Shanghai Study. Plasma SFRP5 level was measured by an enzyme-linked immunosorbent assay. Results: Plasma SFRP5 level was negatively associated with body mass index, waist/hip ratio and fasting blood glucose (all P < 0.001). Lower plasma SFRP5 level was observed in men than in women (4.19 vs 5.13 ng/ml, P < 0.001), in smokers than in nonsmokers (4.34 vs 4.78 ng/ml, P < 0.05). Additionally, plasma SFRP5 level was also lower in diabetes than those without diabetes (4.30 vs 4.81 ng/ml, P < 0.05). Further, an inverse association was observed between SFRP5 and pulse wave velocity as well as carotid intima-media thickness (both P < 0.05). Moreover, multivariate logistic regression analysis showed lower SFRP5 level was associated with increased arterial stiffness in the elderly (OR 0.83, 95% CI 0.71 to 0.99 per 1-SD increase, P < 0.05). Conclusions: Plasma SFRP5 level was inversely correlated with conventional cardiovascular risk factors and low plasma SFRP5 was also significantly associated with arterial stiffening in the elderly Chinese population.

Effect of SFRP5 (Secreted Frizzled–Related Protein 5) on the WNT5A (Wingless-Type Family Member 5A)-Induced Endothelial Dysfunction and Its Relevance With Arterial Stiffness in Human Subjects

SFRP5 (secreted frizzled-related protein 5) is an endogenous inhibitor of WNT5A (wingless-type family member 5a), which has been implicated in atherosclerosis. However, contradictory results have been reported about the role of SFRP5 in atherosclerosis. We aimed to investigate whether SFRP5 could restore WNT5A-induced endothelial dysfunction in vitro and ex vivo. In addition, we sought to determine whether the serum concentration of SFRP5 is associated with atherosclerosis in humans. We measured endothelium-dependent vasorelaxation in the isolated thoracic aorta of Sprague-Dawley rats. In addition, we measured intracellular nitric oxide (NO) in human endothelial cells. The protein abundance of total and phosphorylated JNK (c-Jun N-terminal kinase), AKT (protein kinase B), and endothelial NO synthase was analyzed in human endothelial cells. Circulating SFRP5 and WNT5A levels and brachial-ankle pulse wave velocity were measured in 282 human subjects with type 2 diabetes mellitus. SFRP5 dose dependently restored Wnt5-induced impaired vasorelaxation in rat thoracic aorta by an endothelial NO synthase-dependent mechanism. SFRP5 treatment restored the WNT5A-induced reduction of NO production via endothelial NO synthase in human endothelial cells. WNT5A-induced changes in the phosphorylation of JNK, AKT, and endothelial NO synthase were ameliorated with SFRP5 administration. In humans with type 2 diabetes mellitus, the serum SFRP5 concentration positively correlated with brachial-ankle pulse wave velocity (r=0.146; P=0.024). Multivariate linear regression analysis demonstrated that the serum SFRP5 concentration was independently associated with brachial-ankle pulse wave velocity after adjustment for potential confounders [B (SE)=7.40 (3.35); P=0.028]. Our data suggest the possible compensatory action of SFRP5 against atherosclerosis under conditions of metabolic dysfunction.