The relationship of circulating neuregulin 4 and irisin, and traditional and novel cardiometabolic risk factors with the risk and severity of coronary artery disease.

BACKGROUND AND AIMS: Neuregulin 4 (NRG4) and irisin are adipokines that have been suggested to be associated with cardiometabolic risk factors and coronary artery disease (CAD), but the data are inconclusive. This study aimed to investigate the relationship between circulating NRG4 and irisin and cardiometabolic risk factors with CAD risk and severity. METHODS AND RESULTS: In this cross-sectional study, the presence of CAD and the severity of stenosis (gensini score) were documented based on coronary angiography in 166 adults. Circulating NRG4 and irisin, glucose homeostasis markers, hs-CRP, lipid profiles, blood pressure, and anthropometric measurements were assessed as well. Age (p = 0.005), sex (p = 0.008), SBP (p = 0.033), DBP (p = 0.04), MAP (p = 0.018), FBG (p = 0.012), insulin (p = 0.039) and HOMA-IR (p = 0.01) were significantly associated with odds of having CAD. The final logistic regression model showed that age, sex, HOMA-IR, and MAP were the most important determinants of having CAD. There were no significant associations between circulating irisin and NRG4 with odds of having CAD. The final general linear model showed that being men (ß = 17.303, 95% CI: 7.086-27.52, P = 0.001), age (Aß = 0.712, 95% CI: 0.21-1.214, P = 0.006), HOMA-IR (Aß = 2.168, 95% CI: 0.256 to 4.079, P = 0.027), and NRG4 level (ß = 1.836, 95% CI: 0.119-3.553, P = 0.036) were directly associated with higher gensini score. Participants with the three-vessel disease had a mean increase of about 5 units in circulating irisin compared to those with no clinical CAD (ß = 5.221, 95% CI: 0.454-9.987, p = 0.032). CONCLUSIONS: This study showed that the adipokines NRG4 and Irisin might be associated with the severity of coronary stenosis.

Effects of serum irisin, neuregulin 4, and weight management on obese adolescent girls with polycystic ovary syndrome.

The study is aimed at investigating the association of serum irisin, neuregulin 4 (NRG4), and anti-müllerian hormone (AMH) with adolescent obesity with polycystic ovary syndrome (PCOS) and the efficacy of weight management interventions. Serum levels of irisin, NRG4, AMH, sex steroid hormone, body mass index (BMI), serum insulin, and C-peptide were measured in 52 obese adolescent girls with PCOS (PCOS group) and 43 obese adolescent girls without PCOS (non-PCOS group). The levels of AMH, NRG4, serum irisin, sex steroid hormones, BMI, serum insulin, and C-peptide were evaluated in obese PCOS girls before and after one year weight management. The levels of AMH, serum insulin, NRG4, and total testosterone of PCOS group were significantly higher than those of non-PCOS group. On the contrary, serum irisin and serum C-peptide in PCOS group were significantly lower than that in non-PCOS group. The levels of fat mass, percent body fat, total testosterone, AMH, NRG4, and serum insulin in the obese girls with PCOS showed significant decreases compared with before weight management intervention. On the contrary, after one year of body weight management intervention, serum irisin and serum C-peptide was significantly increased. Adolescent obesity complicated with PCOS is significantly associated with glucose and lipid metabolism and sex steroid hormone disorders, but the exact pathophysiological and clinical features are highly variable. Weight management intervention can significantly improve the clinical symptoms and hematological indicators, serum irisin and NRG4 can be used as two essential biomarkers for evaluating weight management.

Is there a role for neuregulin 4 in human nonalcoholic fatty liver disease?

BACKGROUND: Neuregulin 4 (Nrg4), a novel adipokine enriched in brown adipose tissue has been observed to negatively regulate de novo hepatic lipogenesis and limit nonalcoholic fatty liver disease (NAFLD) progression to nonalcoholic steatohepatitis (NASH) in rodents. However, the role of Nrg4 in human NAFLD remains unclear to date. We analysed Nrg4 plasma levels and its association with liver disease severity together with the transcriptional profile of the Nrg4 pathway in liver and visceral adipose tissue (VAT) of NAFLD patients. METHODS: Plasma Nrg4 levels were measured in 65 NAFLD patients and 43 healthy controls (HC). Hepatic steatosis and fibrosis were diagnosed and quantified with chemical shift MRI and transient elastography respectively. Furthermore, blood lipid levels, HOMA-IR and systemic pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ) were analysed. Microarray analyses to assess differences in the Nrg4 and its receptor family ErbB pathway in liver and VAT from an independent patient group with biopsy proven NAFL (simple steatosis) (n = 4), NASH (n = 5) and normal liver (n = 6) were performed. RESULTS: Plasma Nrg4 levels were not significantly different between NAFLD patients and HC (p = 0.622). Furthermore, plasma Nrg4 levels did not correlate with the hepatic fat fraction (r = -0.028, p = 0.829) and were not significantly different between NAFLD patients with or without hepatic fibrosis (p = 0.087). Finally, the expression profile of 82 genes related to the Nrg4-ErbB pathway in liver and VAT was not significantly different between NAFL, NASH or obese controls. CONCLUSION: Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD.

The Effect of Omega-3 Fatty Acid Supplementation on Serum Adipocytokines, Lipid Profile and Biochemical Markers of Inflammation in Recreational Runners.

BACKGROUND: The study aimed to evaluate the effects of a 3-week ω-3 PUFA supplementation on serum adipocytokines (i.e., adiponectin, leptin), neuregulin-4 (NRG4) and erythrocyte omega-3 (ω-3) fatty acid content, as well as the blood antioxidant defense capacity in non-elite endurance runners. METHODS: Twenty-four runners were randomized into two groups: the supplemented group, who received omega free fatty acids extract containing 142 mg of EPA, 267 mg of DHA, 12 mg of vitamin E and 5 µg of vitamin D, each administrated at a dose of six capsules twice a day for three weeks, or the placebo group. Venous blood samples were withdrawn at the start and at the end of the study protocols to estimate serum biochemical variables. RESULTS: A significantly higher ω-3 index and lower AA/EPA ratio was observed after ω-3 PUFA compared to pre-supplementation levels (p < 0.001 and p < 0.001, respectively). An increase in baseline adiponectin and NRG4 levels, as well as a decrease of leptin concentration and lipid profile improvement, were observed in subjects after a ω-3 PUFA diet. The increased ω-3 index had a significant effect on TNFα levels and a serum marker of antioxidant defense. CONCLUSIONS: The ω-3 PUFA extract with added vitamin E and D supplementation may have a positive effect on the function of the adipocyte tissue, as well as the ability to prevent cardiovascular complications in athletes.

Negative Correlation between Neuregulin-4 and IL-9 Serum Levels in Patients with Coronary Artery Disease.

BACKGROUND: Neuregulin 4 (Nrg4) is a novel adipocytokine that has been proposed to play a role in modulating energy metabolism and pathogeneses of atherosclerosis. However, no published research is available about the mechanisms underlying the anti-atherosclerotic effect of Nrg4. Regarding the close link between adipocytokines and the immune system, we wonder whether there is a relation between Nrg4 and athero-protective cytokines. The aim of this study was to investigate the relationship between serum Nrg4 levels and type 2 cytokines in Iranian patients with coronary artery disease (CAD). METHODS: In this case-control study, 125 CAD patients were compared to 55 healthy controls. The serum concentrations of Nrg4, IL-5, IL-9, and IL-13 were measured using ELISA. The associations of circulating Nrg4 and IL-5, IL-9, IL-13 were assessed using linear regression analyses. RESULTS: Serum concentration of IL-9 was significantly higher in patients compared to the healthy controls (317.9±139 versus 228.3±99.1, P= ˂0.0001). IL-13 and Nrg4 were significantly lower in patients compared to the healthy controls (4.3±3.7 versus 6.1±3.9, P=0.01 and 0.5 versus 1.3, P=0.001 respectively). Multiple linear regression analyses revealed that IL-9 was negatively correlated with Nrg4 (ß= -0.3, P=0.009). CONCLUSION: Our study, for the first time, provides the clinical evidence revealing that circulating Nrg4 concentrations are inversely correlated with IL-9 in Iranian patients with CAD, suggesting that the protective role of Nrg4 on atherosclerosis may be, in part, mediated by the proatherogenic cytokine, IL-9.

Neuregulins: protective and reparative growth factors in multiple forms of cardiovascular disease.

Neuregulins (NRGs) are protein ligands that act through ErbB receptor tyrosine kinases to regulate tissue morphogenesis, plasticity, and adaptive responses to physiologic needs in multiple tissues, including the heart and circulatory system. The role of NRG/ErbB signaling in cardiovascular biology, and how it responds to physiologic and pathologic stresses is a rapidly evolving field. While initial concepts focused on the role that NRG may play in regulating cardiac myocyte responses, including cell survival, growth, adaptation to stress, and proliferation, emerging data support a broader role for NRGs in the regulation of metabolism, inflammation, and fibrosis in response to injury. The constellation of effects modulated by NRGs may account for the findings that two distinct forms of recombinant NRG-1 have beneficial effects on cardiac function in humans with systolic heart failure. NRG-4 has recently emerged as an adipokine with similar potential to regulate cardiovascular responses to inflammation and injury. Beyond systolic heart failure, NRGs appear to have beneficial effects in diastolic heart failure, prevention of atherosclerosis, preventing adverse effects on diabetes on the heart and vasculature, including atherosclerosis, as well as the cardiac dysfunction associated with sepsis. Collectively, this literature supports the further examination of how this developmentally critical signaling system functions and how it might be leveraged to treat cardiovascular disease.

Clinical significance of serum concentrations of neuregulin-4, in acute coronary syndrome.

Acute coronary syndrome (ACS) is closely associated with an increased risk of death. Nrg4, a novel adipocytokine, has negative correlations with indicators of metabolic syndrome. Here, we investigated whether circulating Nrg4 associates with the prevalence of ACS. In this case-control study, a total of 257 subjects (144 patients with ACS and 56 patients diagnosed with stable angina pectoris (SAP)) compared to 57 healthy controls. Serum Nrg4 and hs-CRP concentrations were determined by ELISA. The associations of circulating Nrg4 with other clinical parameters were also analyzed. Serum levels of Nrg4 were lower in patients compared to the control subjects (0.7 ± 0.53 ng/mL versus 1.1 ± 0.9 ng/mL, P = 0.018). There was a significant association between higher Nrg4 level and lower risk of ACS (OR = 0.15; 95%CI = 0.02-0.9; P = 0.046), but not with SAP. This association was independent of potential confounders including traditional cardiovascular risk factors. The distribution of patients with no, 1, 2 and 3 vessel stenosis was significantly different in Nrg4 quartiles. Patients in the lower quartile of Nrg4 were more likely to experience 3 vessel diseases. Serum levels of Nrg4 correlated negatively with HDL-cholesterol in ACS patients. Decreased serum levels of Nrg4 might be an independent risk factor for ACS.

Is Neuregulin-4 a predictive marker of microvascular complications in type 2 diabetes mellitus?

BACKGROUND AND AIMS: Neuregulin-4 (Nrg-4) is a new adipokine released from brown adipose tissue. It plays pivotal role in regulating systemic energy balance, glucose and lipid metabolism and in reducing chronic inflammation. We aimed to investigate the relation between diabetic microvascular complications (DMC) and serum (Nrg-4) levels in patients with type 2 diabetes mellitus. METHODS: Patients with type 2 diabetes mellitus were divided into DMC and diabetic patients without microvascular complications (non-DMC). Nrg-4 levels of the patients were compared. RESULTS: Fifty and 29 patients enrolled to the DMC and non-DMC groups, respectively. Nrg-4 was 1.23 (0.02-5.1) ng/mL and 2.5 (0.21-6.01) ng/mL in DMC and in non-DMC groups, respectively (P < .001). In patients with DMC, FPG was 189.5 (89-446) mg/ dL, whereas it was 128 (95-278) mg/dL in non-DMC diabetic patients (P < .001). HbA1c was also significantly higher in the DMC group than in the non-DMC group (P < .001). Negative correlation was found between Nrg-4 and FPG (r = -0.231, P = .03), HBA1c (r = -0.312, P = .003) and microalbuminuria (r = -0.277, P = .009). Logistic regression analysis showed a 1-unit decrease in Nrg-4 to increase the presence of DMC by 1.9 times. The best cut-off value of Nrg-4 was 1.56 ng/mL with 82.1% sensitivity and 64% specificity, in predicting DMC. CONCLUSION: In patients with diabetes, Nrg-4 levels may be a good predictor of early detection of one or more DMC, as microvascular dysfunction in an organ system is considered to be an initial onset of subclinical systemic damage.

Association between circulating neuregulin4 levels and diabetes mellitus: A meta-analysis of observational studies.

INTRODUCTION: Neuregulin 4 (Nrg4) was proven as a brown fat-enriched secreted factor that can regulate glucose and lipid metabolism. However, the association between circulating Nrg4 levels and diabetes mellitus (DM) in human remains unclear. We conducted a meta-analysis to investigate association of circulating Nrg4 with DM. METHODS: Observational studies comparing circulating Nrg4 levels in diabetes patients and health controls were included. Circulating Nrg4, correlation coefficients of clinical indices and circulating Nrg4 were pooled by meta-analysis. RESULTS: Seven studies were included. The pooled results indicated there were no significant difference in the circulating Nrg4 between diabetes patients and controls (SMD = 0.18, 95%CI = -0.06 to 0.42, P = 0.143). However, diabetes patients had higher circulating Nrg4 than their controls in cross-sectional studies (SMD = 0.55, 95%CI = 0.36 to 0.73, P<0.001). None of the renal function and metabolic syndrome markers were correlated with circulating Nrg4, whereas the HbA1c and BMI were positively correlated (rs = 0.09, 95%CI = 0.03 to 0.16, P = 0.005; rs = 0.20, 95%CI = 0.07 to 0.34, P = 0.003; respectively). CONCLUSION: Our findings suggested circulating Nrg4 may play a role in in the development of DM in cross-sectional studies and circulating Nrg4 might be associated with imbalance in glucose metabolism and obesity.

The brown fat-secreted adipokine neuregulin 4 is decreased in human and murine chronic kidney disease.

OBJECTIVE: Neuregulin 4 (NRG4) has recently been introduced as a novel brown adipose tissue (BAT)-secreted adipokine with beneficial metabolic effects in mice. However, regulation of Nrg4 in end-stage kidney disease (ESKD) and type 2 diabetes mellitus (T2DM) has not been elucidated, so far. DESIGN/METHODS: Serum NRG4 levels were quantified by ELISA in 60 subjects with ESKD on chronic hemodialysis as compared to 60 subjects with an estimated glomerular filtration rate >50 mL/min/1.73 m2 in a cross-sectional cohort. Within both groups, about half of the patients had a T2DM. Furthermore, mRNA expression of Nrg4 was determined in two mouse models of diabetic kidney disease (DKD) as compared to two different groups of non-diabetic control mice. Moreover, mRNA expression of Nrg4 was investigated in cultured, differentiated mouse brown and white adipocytes, as well as hepatocytes, after treatment with the uremic toxin indoxyl sulfate. RESULTS: Median serum NRG4 was significantly lower in patients with ESKD compared to controls and the adipokine was independently associated with a beneficial renal, glucose and lipid profile. In mice with DKD, Nrg4 mRNA expression was decreased in all adipose tissue depots compared to control mice. The uremic toxin indoxyl sulfate did not significantly alter Nrg4 mRNA expression in adipocytes and hepatocytes, in vitro. CONCLUSIONS: Circulating NRG4 is independently associated with a preserved renal function and mRNA expression of -Nrg4 is reduced in adipose tissue depots of mice with DKD. The BAT-secreted adipokine is further associated with a beneficial glucose and lipid profile supporting NRG4 as potential treatment target in metabolic and renal disease states.

Association between circulating neuregulin 4 levels and metabolic, aterogenic, and AMH profile of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a metabolic disorder associated with obesity and energy metabolic system disturbances in adipose tissue. Neuregulin 4 (NRG4), which is secreted by adipose tissue, regulates energy metabolism. In the present study, we aimed to evaluate the association between serum NRG4 levels in obese and normal weight PCOS patients. This cross-sectional study was conducted at a tertiary hospital in Turkey from April to August 2017. We included 148 women who were divided into four groups as follows: 40 normal weight and 39 obese PCOS women diagnosed according to the Rotterdam criteria as well as 38 normal weight and 31 obese, age-matched, non-hyperandrogenemic women with a regular menstrual cycle (controls). Levels of serum NRG4, anti-Müllerian hormone (AMH), fasting blood glucose (FBG), insulin, and high-sensitivity C-reactive protein (hs-CRP); lipid and hormone profiles; insulin resistance indices [homeostasis model assessment of insulin resistance (HOMA-IR)];and anthropometric parameters were evaluated. Serum NRG4 levels were elevated in the normal weight PCOS group than in the control group. Moreover, serum NRG4 levels were higher in the obese PCOS group than in the normal weight PCOS and obese control groups (p < .01). Serum NRG4 levels were positively correlated with body mass index (BMI); waist/hip ratio; HOMA-IR; and levels of triglycerides, hs-CRP, FBG, insulin, AMH, and dehydroepiandrosterone sulphate. Multiple regression analyses revealed that serum NRG4 levels were independently associated with BMI. Obesity appears to be the most influential factor for NRG4 secretion in PCOS patients. Management of obesity may be a key factor for resolving PCOS-related metabolic abnormalities and fertility problems. Impact Sstatement What is already known on this subject? PCOS is a dynamic syndrome with different clinical and metabolic features during the reproductive age. PCOS is associated with various metabolic abnormalities, such as insulin resistance (IR), glucose intolerance, dyslipidemia, and obesity (particularly visceral obesity) as well as long-term complications, such as type 2 diabetes and cardiovascular diseases. Neuregulin 4 (NRG4), which is secreted by adipose tissue, regulates energy metabolism. What do the results of this study add? To the best of our knowledge, this was the first study investigating NRG4 levels in PCOS patients with different BMIs. Obesity appears to be the most influential factor for NRG4 secretion in these patients. Managing obesity may be a key factor for resolving PCOS-related metabolic abnormalities. What are the implications of these findings for clinical practice and/or further research? Further research in PCOS is warranted to ameliorate obesity, and our study can provide basis for future studies investigating NRG4 levels in PCOS patients with different phenotypes as well as studies of gene polymorphisms, AMH, and infertility and can contribute to the elucidation of problems related to the pathophysiology of PCOS.

Decreased plasma neuregulin 4 levels are associated with peripheral neuropathy in Chinese patients with newly diagnosed type 2 diabetes: A cross-sectional study.

Neuregulin-4 (Nrg4) is a novel adipokine associated with obesity, hyperglycemia, insulin resistance, dislipidemia, inflammation, and oxidative stress in mice and humans. However, no report has demonstrated the relationship of circulating Nrg4 with diabetic peripheral neuropathy (DPN). The objective of our study was to investigate the relationship between circulating Nrg4 and DPN in a cross-sectional study. Circulating Nrg4 levels were determined with an enzyme-linked immunosorbent assays kit in 132 newly diagnosed type 2 diabetes mellitus (nT2DM) patients and 41 normal controls (NC group). The associations of circulating Nrg4 with other parameters were also analyzed. Circulating Nrg4 levels were significantly lower in nT2DM patients with no DPN than in NC subjects, and were further markedly decreased in nT2DM patients with DPN (P < 0.01 or P < 0.05). Circulating Nrg4 levels were progressively decreased with an increasing number of abnormal DPN screening (P for trend < 0.01). Circulating Nrg4 levels correlated negatively with 8-iso-prostaglandin F2α (8-iso-PGF2α), high-sensitivity C-reactive protein (hs-CRP) and vibration perception threshold (VPT) (all P < 0.01), and 8-iso-PGF2α, hs-CRP, glycated hemoglobin A1c and VPT were independently related factors to circulating Nrg4 in nT2DM patients (P < 0.01 or P < 0.05). Moreover, circulating Nrg4 was significantly associated with the development of DPN even after controlling for anthropometric, biochemical and clinical parameters. Additionally, the analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating Nrg4 to predict DPN was 1.58 ng/mL (sensitivity 90.91%, specificity 54.55%, and area under the curve 0.716). These findings together suggested that circulating Nrg4 levels were reduced in DPN patients and Nrg4 may be a novel adipokine associated with inflammation, oxidative stress, and long-term glycemic control in nT2DM patients.

Association of Circulating Neuregulin-4 with Presence and Severity of Coronary Artery Disease.

Neuregulin-4 (Nrg4) is a newly discovered adipokine that is synthesized in many tissues and plays an important role in modulating systemic energy metabolism and in the development of metabolic disorders. However, little is known about the relationship between Nrg4 and coronary artery disease (CAD). In this study, we investigated the association between Nrg4 and the presence and severity of CAD.We enrolled 73 patients diagnosed by coronary angiography (CAG) as having CAD and 32 controls. The CAD group was divided into two subgroups according to their SYNTAX score. Plasma levels of Nrg4 were measured in all participants and compared among different groups. The relationship between Nrg4 and CAD was analyzed. Receiver operating characteristic (ROC) analysis was conducted to evaluate the usefulness Nrg4 in assessing the presence and severity of CAD.Nrg4 levels were negatively associated with the SYNTAX score (r = -0.401, P = 0.000). The patients with a higher SYNTAX score had significantly lower Nrg4 levels as compared with the low SYNTAX score subgroup and the controls (P < 0.05). The Nrg4 levels of the low SYNTAX score subgroup were much lower than controls (P < 0.05). Furthermore, an association between Nrg4 and CAD (odds ratio, 0.279; 95% confidence interval, 0.088-0.882) was observed. Nrg4 had 43.8% sensitivity and 96.9% specificity for identifying CAD, and 73.1% sensitivity and 87.3% specificity for identifying patients who had severe coronary artery lesions.Nrg4 levels were found to be inversely associated with the presence and severity of CAD.

Decreased serum neuregulin 4 levels associated with non-alcoholic fatty liver disease in children with obesity.

Neuregulin 4 (Nrg4), a newly identified adipokine secreted by brown adipose tissue, is hypothesised to play a crucial role in metabolism. The present study aimed to evaluate the association between serum Nrg4 levels and non-alcoholic fatty liver disease (NAFLD) in children with obesity in China. A total of 123 children with obesity were included in this study. Anthropometric and biochemical parameters were measured in all subjects. NAFLD was diagnosed using ultrasonography. The serum levels of Nrg4, leptin and adiponectin were measured by enzyme-linked immunosorbent assay. NAFLD was identified in 58 children with obesity (47.2%). Serum Nrg4 levels were significantly lower in the NAFLD group (2.24 [1.20, 3.22] ng/mL) than in the control group (5.50 [2.45, 10.85] ng/mL) (p < 0.001). Serum Nrg4 levels were negatively correlated with most of the anthropometric and biochemical parameters (p < 0.05) but were positively correlated with high-density lipoprotein cholesterol (p < 0.05). In multiple stepwise regression analyses, serum Nrg4 levels were independently related with WHtR (ß = -2.009, p = 0.048) and homeostasis model assessment of insulin resistance (ß = -0.524, p = 0.005). Furthermore, a multivariable logistic regression analysis of NAFLD prediction by Nrg4 revealed an odds ratio of 0.129 (95% confidence interval: 0.028-0.587, p < 0.01). The receiver operating characteristic curve analysis of the diagnostic value of using serum Nrg4 levels to differentiate NAFLD in children with obesity showed that the area under the curve was 0.723; the cutoff for serum Nrg4 levels to have diagnostic value for predicting NAFLD in children with obesity was 3.39 ng/mL. Elevated Nrg4 is associated with a decreased risk of NAFLD in children with obesity.

Effects of endogenous serum neuregulin-1ß on morbidity and mortality in patients with heart failure and left ventricular systolic dysfunction.

CONTEXT: Improved left ventricular ejection fraction (LVEF) following administration of recombinant human Neuregulin-1ß (NRG), epidermal growth factor (EGF) involved in cardiomyocyte repair/survival, has been observed in patients with systolic heart failure (HF). METHODS: Serum NRG was measured by ELISA in 248 patients with NYHA class I-IV HF. RESULTS: NRG exhibited a marginally significant effect on LVEF trajectory over 11 months (p = 0.07). There is no apparent level of NRG that predicts improved survival. CONCLUSIONS: There is a potential relationship between serum NRG and improved LVEF, indicating the need to investigate the utility of NRG in predicting HF outcomes, including LVEF maintenance.

Plasma Neuregulin 4 Levels Are Associated with Metabolic Syndrome in Patients Newly Diagnosed with Type 2 Diabetes Mellitus.

Neuregulin 4 (Nrg4) has been proposed to play a role in the pathogeneses of obesity, insulin resistance, and dyslipidemia. However, information about the link between Nrg4 and metabolic syndrome (MetS) is scarce, especially in patients with newly diagnosed type 2 diabetes mellitus (nT2DM). This study aimed at investigating whether Nrg4 is associated with MetS in nT2DM patients. A total of 311 patients with nT2DM were recruited. Plasma Nrg4 concentration was determined by ELISA. Plasma Nrg4 concentration was lower in nT2DM patients with MetS than in nT2DM patients without MetS (P = 0.001). Nrg4 concentration showed negative correlations with most of the analyzed indicators of MetS. MetS was less prevalent among subjects in the highest quartile of plasma Nrg4 concentration than among those in the lowest quartile (P < 0.01). Age- and sex-adjusted plasma Nrg4 concentrations were positively correlated with concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A (both P < 0.05) and negatively correlated with triglyceride, high-sensitivity C-reactive protein (hs-CRP), and gamma-glutamyltransferase concentrations, neutrophil count, and white blood cell (WBC) count (all P < 0.05). In multivariate analysis, Nrg4 was independently associated with hs-CRP level, WBC count, and HDL-C level (P = 0.001 or P < 0.05). Multiple logistic regression analysis of MetS prediction by Nrg4 revealed an odds ratio of 0.560 (95% CI: 0.374-0.837; P < 0.01). Decreased plasma Nrg4 levels, which may be associated with augmented oxidative stress, inflammation, and dyslipidemia, might be involved in the development of MetS in nT2DM patients.

Clinical significance of neuregulin 4 (NRG4) in gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is defined as glucose intolerance detected during pregnancy. GDM is increasing worldwide and is associated with adverse maternal and fetal outcomes. Neuregulin 4 (NGR4) is epidermal growth factor like signaling molecule. It plays an important role in cell to cell communication furthermore recent studies indicate that NRG4 may work as a novel adipokine with a possible role in maintaining energy and metabolic homeostasis. The aim of the present study was to assess serum NRG4 levels along with several metabolic parameters in patients diagnosed with gestational diabetic mellitus. MATERIALS AND METHODS: In this prospective cross-sectional study, the study group was composed of 63 women with GDM and 64 healthy pregnant women matched for age, body mass index (BMI) and gestational age. Blood samples were collected at the 24-28th gestational weeks. Serum NRG4, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides, glucose levels during 75-gr OGTT, fasting insulin, glycosylated hemoglobin A1c (HbA1c), alanine aminotransferase (ALT) and creatinine levels were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) values were calculated. RESULTS: Serum NRG4 values were significantly elevated in the GDM group compared to the control group (p < .001). Multivariate linear regression analyzes revealed that BMI (ß = 0.910, p < .001), glucose 2-h OGTT (ß = 0.866, p < .001) and HOMA-IR (ß = 0.222, p < .001) independently and positively predicted NRG4 levels. CONCLUSIONS: Serum NRG4 levels were associated with metabolic parameters of GDM. The present study can be considered to be a guide for future studies to clarify the pathophysiology of NGR4 in GDM patients.

The brown-fat-secreted adipokine neuregulin 4 is decreased in gestational diabetes mellitus.

AIMS: Neuregulin 4 has recently been recognized as a novel adipokine secreted by brown adipose tissue (BAT), with beneficial effects on murine insulin resistance and hepatic steatosis. Yet, thus far, neither regulation of neuregulin 4 in gestational diabetes mellitus (GDM) nor its longitudinal changes in the peripartum period have been elucidated. METHODS: Circulating neuregulin 4 levels were measured by ELISA in 74 women with GDM and 74 healthy, gestational-age-matched controls. Also, neuregulin 4 was quantified during pregnancy and compared with postpartum levels in a follow-up study of 25 women with previous GDM and 25 healthy control women. RESULTS: Women with GDM had lower median serum levels of the novel BAT-secreted adipokine neuregulin 4 (3.0µg/L) compared with healthy (non-GDM) pregnant controls (3.5µg/L; P=0.020), and the area under the glucose curve (AUCGlucose) was an independent and negative predictor of circulating neuregulin 4 (P=0.033). Also, median postpartum serum concentrations of neuregulin 4 (3.2µg/L) were not significantly different from prepartum levels (2.8µg/L; P=0.328). In addition, neuregulin 4 was positively and independently associated with irisin (P=0.009), but not other BAT-secreted adipokines. CONCLUSION/INTERPRETATION: Women with GDM have significantly lower circulating neuregulin 4 levels compared with healthy pregnant controls, and the AUCGlucose is negatively and independently associated with neuregulin 4 during pregnancy. Neuregulin 4 is positively correlated with irisin during pregnancy, as well as in a longitudinal fashion. Future studies are now needed to better elucidate the precise pathomechanisms of the regulation of BAT-secreted adipokines during pregnancy.

Increased serum neuregulin 4 levels in women with polycystic ovary syndrome: A case-control study.

Neuregulin 4 (NRG4) is an adipokine that is synthesized in many tissues and has been shown to be associated with the development of obesity and metabolic disorders in animals and humans. The aim of this study is to investigate the relationship between serum NRG4 levels and various metabolic parameters in women with PCOS. This cross-sectional study included 40 women with PCOS and 40 age- and BMI-matched controls without PCOS. NRG4, fasting blood glucose (FBG), insulin, hs-CRP, LDL-C, HDL-C, SHBG, DHEA-SO4 and total-testosterone levels were measured in all the participants. HOMA-IR was used to calculate the insulin resistance. Serum NRG4 levels were higher in women with PCOS than in healthy women (24.89 ± 9.32 [ng/mL] vs. 18.98 ± 6.40 [ng/mL], p = 0.002). FBG, LDL-C, HDL-C, LH, SHBG, FAI, DHEA-SO4, insulin, hs-CRP, HOMA-IR and total-testosterone levels were significantly higher in women with PCOS than controls. Circulating NRG4 levels were positively correlated with HOMA-IR, insulin and hs-CRP for both groups. There was a positive correlation between NRG4 and FBG in the PCOS group. HOMA-IR and hs-CRP were associated with NRG4. The high concentration of circulating NRG4 in PCOS may be associated with insulin resistance and low-grade chronic inflammation.

Decreased plasma neuregulin 4 concentration is associated with increased high-sensitivity C-reactive protein in newly diagnosed type 2 diabetes mellitus patients: a cross-sectional study.

AIMS: Inflammation has been reported to be involved in the pathogenesis of atherosclerosis. This principal objective of this study was to investigate if the secretion of neuregulin 4 (Nrg4), a soluble protein associated with metabolic syndrome and subclinical cardiovascular disease, is correlated with the inflammation marker high-sensitivity C-reactive protein (hs-CRP) in patients with newly diagnosed type 2 diabetes mellitus (nT2DM). METHODS: A study group of 311 nT2DM patients was divided into three subgroups based on hs-CRP tertiles. Multiple linear regression was conducted to explore the association between plasma Nrg4 and hs-CRP levels. RESULTS: The nT2DM patients with the highest hs-CRP levels (>2.46 mg/L) exhibited higher atherogenic coefficients and atherogenic index of plasma (AIP) levels, but lower levels of plasma Nrg4, as compared to those with the lowest hs-CRP levels (<0.63 mg/L). Plasma Nrg4 levels were inversely associated with white blood cell count, hs-CRP, and AIP and positively associated with high-density lipoprotein cholesterol (HDL-C), before and after adjustment for age, gender, body mass index (BMI), and body fat percentage (P < 0.01 or P < 0.05). hs-CRP was the factor most strongly associated with plasma Nrg4 levels. CONCLUSIONS: These results indicate that lower plasma Nrg4 levels may be associated with elevated hs-CRP in nT2DM patients. It generates the hypothesis that decreased levels of Nrg4 may trigger the development of atherosclerosis through its proinflammatory effects. These findings need to be confirmed by further prospective studies.