Nrg4 Levels Research Articles

A comparison of brown fat tissue related hormone levels in metabolically healthy and unhealthy individuals with obesity.

One of the key functions of brown adipose tissue is its positive impact on metabolism. This study aimed to examine the potential involvement of brown fat-related hormones in the development of metabolically healthy obesity. Specifically, we sought to compare the levels of NRG4, FGF21, and irisin between metabolically healthy and unhealthy individuals with obesity. Patients with BMI ≥ 30 kg/m2 and aged between 20 and 50 years were included in the study. Among these patients, those who did not have any metabolic syndrome criteria except for increased waist circumference were defined as metabolically healthy obese. Age, gender, BMI, body fat, and muscle mass, matched metabolically healthy and unhealthy obese groups were compared in terms of FGF21, irisin, and NRG4 levels. Metabolically healthy and unhealthy obese groups were similar in terms of age and gender. There was no difference between the two groups in terms of BMI, weight, total body fat, muscle, fat-free mass, distribution of body fat and muscle mass. No statistically significant difference was found between irisin, NRG4, and FGF21 levels between metabolically healthy and unhealthy individuals with obesity. It was found that irisin had a significant inverse correlation with BMI and body fat percentage. The present study showed no difference between metabolically healthy and unhealthy obese individuals in terms of irisin, FGF21, and NRG4 levels. The weak association between irisin and BMI and body fat percentage may suggest a potential link between irisin with metabolic health.

Lipid metabolic reprogramming mediated by circulating Nrg4 alleviates metabolic dysfunction-associated steatotic liver disease during the early recovery phase after sleeve gastrectomy

BackgroundThe metabolic benefits of bariatric surgery that contribute to the alleviation of metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. However, the processes and mechanisms underlying the contribution of lipid metabolic reprogramming after bariatric surgery to attenuating MASLD remain elusive.MethodsA case–control study was designed to evaluate the impact of three of the most common adipokines (Nrg4, leptin, and adiponectin) on hepatic steatosis in the early recovery phase following sleeve gastrectomy (SG). A series of rodent and cell line experiments were subsequently used to determine the role and mechanism of secreted adipokines following SG in the alleviation of MASLD.ResultsIn morbidly obese patients, an increase in circulating Nrg4 levels is associated with the alleviation of hepatic steatosis in the early recovery phase following SG before remarkable weight loss. The temporal parameters of the mice confirmed that an increase in circulating Nrg4 levels was initially stimulated by SG and contributed to the beneficial effect of SG on hepatic lipid deposition. Moreover, this occurred early following bariatric surgery. Mechanistically, gain- and loss-of-function studies in mice or cell lines revealed that circulating Nrg4 activates ErbB4, which could positively regulate fatty acid oxidation in hepatocytes to reduce intracellular lipid deposition.ConclusionsThis study demonstrated that the rapid effect of SG on hepatic lipid metabolic reprogramming mediated by circulating Nrg4 alleviates MASLD.

Effect of metformin as an add-on therapy on neuregulin-4 levels and vascular-related complications in adolescents with type 1 diabetes: A randomized controlled trial

BackgroundInflammation is closely associated with atherosclerosis and plays a crucial role in the development of cardiovascular disease. Metformin sensitizes body cells to insulin, which may cause a reduction of atherogenic lipid fractions. Low neuregulin-4 (Nrg-4) levels, an adipokine, are linked to obesity, insulin resistance, impaired glucose tolerance and type 2 diabetes. ObjectivesWe assessed the effect of oral supplementation with metformin on glycemic control, neuregulin-4 levels and carotid intima media thickness (CIMT) as a marker for subclinical atherosclerosis in adolescents with type 1 diabetes mellitus (T1DM) and microvascular complications. MethodsThis randomized placebo-controlled trial included 80 type 1 diabetic patients with microvascular complications who were randomly divided to receive either 24 weeks of metformin 500 mg/day or matching placebo. Fasting blood glucose (FBG), HbA1c, C-reactive protein (CRP), urinary albumin creatinine ratio (UACR), lipid profile, Nrg-4 and CIMT were assessed at baseline and study end. ResultsBoth groups were well-matched as regards baseline clinical and laboratory data (p greater than 0.05). After 24-weeks, metformin therapy for the intervention group resulted in a significant decrease of HbA1c, CRP, UACR, total cholesterol and CIMT while Nrg-4 levels were increased compared with baseline levels (p < 0.001) and with placebo group(p < 0.001). Baseline Nrg-4 levels were negatively correlated to FBG, HbA1c, total cholesterol, CRP and CIMT. Metformin was well-tolerated. ConclusionsOral metformin supplementation once daily for 24 weeks as an adjuvant therapy to intensive insulin in pediatric T1DM was safe and effective in improving glycemic control, dyslipidemia and Nrg-4 levels; hence, it decreased inflammation, microvascular complications and subclinical atherosclerosis.

Differential Effects of Exercise Programs on Neuregulin 4, Body Composition and Cardiometabolic Risk Factors in Men With Obesity.

BackgroundNeuregulin 4 (Nrg4) is an adipokine that is sensitive to energy expenditure and with a potential role in metabolic homeostasis and obesity. This study examined the effects of 12 weeks of three different exercise training protocols on Nrg4 levels, cardiometabolic risk factors, and body composition parameters in men with obesity.MethodsSixty adult men with obesity (Mean ± SD; age: 27.60 ± 8.4 yrs.; height: 168.4 ± 2.6 cm; weight: 96.7 ± 7.2 kg) were randomly allocated into four equal (n = 15) groups: High- Intensity Interval Training (HIIT), Circuit Resistance Training (CRT), Moderate Intensity Continuous Training (MICT) or a control group. The HIIT protocol involved six bouts of 3-min high-intensity exercise (90% VO2peak) followed by 3-min low-intensity exercise (50% VO2peak). The CRT group performed three circuits of resistance training, where each circuit included 11 exercises at 20% of one-repetition maximum (1RM) and 70% of VO2peak, and with a work-to-rest ratio of 2:1 (40-s exercise and 20-s rest) and 60-s recovery between circuits. The MICT group performed 36 min of exercise at 70% of VO2peak. All measurements were taken 72 h before and after the first and last training sessions.ResultsThere were significant differences between the groups in fat-free mass (FFM), (effect size (ES): 0.78), fat mass (ES: 0.86), VO2peak (ES: 0.59), high-density lipoprotein cholesterol (HDL-C) (ES: 0.83), low-density lipoprotein (LDL-C) (ES: 0.79), total cholesterol (TC) (ES: 0.90), triglyceride (TG) (ES: 0.52) glucose (ES: 0.39), insulin (ES: 0.61), HOM-IR (ES: 0.91) and Nrg4 (ES: 0.98) (p < 0.05). There were no significant changes in very-low-density lipoprotein cholesterol (VLDL-C) (ES: 0.13) levels, or body weights (ES: 0.51) (p > 0.05). Levels of Nrg4 were negatively correlated with LDL-C, TC, TG, VLDL-C, glucose, insulin, HOMA-IR (p < 0.05) and positively with HDL-C (p < 0.05).ConclusionOur results suggest that HIIT and CRT protocols have greater effects than MICT protocol on Nrg4 levels, metabolic and cardiovascular risk factors, and body composition variables in men with obesity.

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

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. 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. 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. Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD.

Adiposity Measurements and Metabolic Syndrome Are Linked Through Circulating Neuregulin 4 and Adipsin Levels in Obese Adults.

BackgroundAdiposity and adipokines are associated with metabolic disorders, but little is known regarding that whether adiposity measurements link metabolic syndrome (MetS) through circulating neuregulin 4 (Nrg4) and adipsin levels.Materials and MethodsA total of 1212 subjects with a waist circumference greater than 90 cm for men or 80 cm for women were enrolled from a Chinese community. Circulating Nrg4 and adipsin levels were measured using commercial kits. Mediation analyses of circulating Nrg4 and adipsin were performed in the study using linear and logistic regression.ResultsSubjects with MetS had higher waist circumference, visceral fat level, and circulating adipsin level, and lower levels of circulating Nrg4 and muscle mass to visceral fat (MVF) ratio (all P < 0.05). In multivariable logistic regression analyses, after adjusting for confounding variables, per standard deviation (SD) increase in waist circumference and visceral fat level were significantly associated with increased odds of MetS [OR (95% CI), 1.42 (1.22–1.64); 2.20 (1.62–2.99); respectively]; and per SD reduction in MVF ratio was significantly associated with reduced odds of MetS [OR (95% CI), 0.65 (0.55–0.77)]. In the mediation analyses, both circulating Nrg4 and adipsin levels mediated the association between waist circumference (8.31% and 18.35%, respectively), visceral fat level (7.50% and 9.98%, respectively), and MVF ratio (5.80% and 9.86%, respectively) and MetS after adjustments.ConclusionThese findings indicate that adiposity measurements and MetS are linked through circulating Nrg4 and adipsin levels in obese adults, suggesting that circulating Nrg4 and adipsin levels might be potential predictors for management of MetS.

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

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). 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. 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 (β= -0.3, P=0.009). 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.

Changes of circulating neuregulin 4 and its relationship with 25-hydroxy vitamin D and other diabetic vascular complications in patients with diabetic peripheral neuropathy

BackgroundNeuregulin 4 (Nrg4) is a novel neurotrophic adipokine associated with the development of diabetic peripheral neuropathy (DPN), however, the pathological mechanism remains poorly understood. The purpose of our study was to investigate the association of circulating Nrg4 with DPN and 25-hydroxy vitamin D [25(OH)D], a multifunctional secosteroid hormone that regulates other neurotrophic factors and adipokines gene expression, and other diabetic vascular complications.MethodsCirculating Nrg4 levels were measured with an ELISA kit in 164 newly diagnosed type 2 diabetes mellitus (nT2DM) patients. The relationship between circulating Nrg4 and DPN and other parameters was analyzed.ResultsCirculating Nrg4 levels were significantly lower in nT2DM patients with DPN than those without, and subjects in the highest quartile of circulating Nrg4 had significantly lower vibration perception threshold (VPT), the prevalence of DPN, the proportion of persons with VPT > 25 V, and significantly higher circulating 25(OH)D (all P < 0.01). Moreover, circulating Nrg4 was positively and independently associated with 25(OH)D, and was negatively with VPT (P < 0.01 or P < 0.05), but showed no associations with the prevalence of peripheral arterial disease, diabetic nephropathy, and diabetic retinopathy (all P > 0.05). Additionally,the prevalence of DPN and risk of DPN development were progressively decreased with increasing circulating Nrg4 quartiles, independently of potential confounding factors.ConclusionsThese data demonstrate that decreased levels of circulating Nrg4 might lead to the development of DPN through its close interaction with circulating 25(OH)D not with other diabetic vascular complications. Further prospective studies are needed to identify our findings in these populations.

Clinical importance of neuregulin-4 and its receptor ErbB4 in periodontal disease pathogenesis.

The aim of this clinical trial was to evaluate the levels of Neuregulin-4 (Nrg4), Erb-b2 receptor tyrosine kinase 4 (ErbB4), interleukin (IL)-6, IL-10, nitric oxide synthase (NOS)-2, and arginase (Arg)-1 in periodontal health and disease. This study includes systemically healthy 20 periodontally healthy (H), 20 gingivitis (G), 20 stage II periodontitis (P1), and 20 stage III periodontitis (P2) subjects. Periodontal clinical measurements and samples of gingival crevicular fluid (GCF) and serum were obtained at baseline and 4weeks after non-surgical periodontal treatment (NSPT). Enzyme-linked immunosorbent assay (ELISA) was used to determine ErbB4, Nrg4, IL-6, IL-10, NOS2, and Arg1 levels in all samples. GCF ErbB4 and Nrg4 total amounts and IL-6/IL-10 ratio were significantly higher in G, P1, and P2 groups than H group. Serum NOS2 levels were significantly lower, whereas serum Arg1 levels were higher in H group than the others. The GCF levels of ErbB4 and Nrg4 were significantly decreased after NSPT in G, P1, and P2 groups. Additionally, the GCF levels of ErbB4 and Nrg4 were positively correlated with all clinical parameters and IL-6/IL-10 ratio. Nrg4 and its receptor ErbB4 might have crucial roles in the pathogenesis of periodontal disease. These results should be verified with future prospective studies to further clarify the exact role of those biomarkers.

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

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. 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. 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 1.56ng/mL with 82.1% sensitivity and 64% specificity, in predicting DMC. 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.

Differences in Neuregulin 4 Expression in Children: Effects of Fat Depots and Obese Status

ABSTRACT Purpose To observe the expression of Nrg4, uncoupling protein-1 (UCP1), tumor necrosis factor α (TNFα), CD31, VE-cadherin/CDH5 and vascular endothelial growth factor A (VEGF-A) mRNA in abdominal subcutaneous (SC), omental (OM) adipose tissue in children with relation to anthropometric parameters. Further to verify the effect of inflammatory mediators on Nrg4 and UCP1 mRNA expression in adipocytes. Methods Paired SC and OM adipose tissues were obtained from 58 children. In vitro, the adipocytes isolated from primary inguinal adipose tissue of mice were treated with TNFα (50 ng/ml) for 12–48 h. mRNA levels of Nrg4, UCP1 and TNFα were determined by real-time PCR. Results Nrg4, UCP1, VEGF-A and CDH5 mRNA levels in SC were significantly higher than those in OM adipose tissue and the mRNA level of TNFα showed the opposite result. Moreover, Nrg4 and UCP1 mRNA in SC were significantly lower in overweight children compared to normal weight children. Nrg4 in SC and OM was negatively associated with BMISDS, WHtR. CDH55 mRNA in OM was negatively associated with WHR. VEGF-A was positively correlated with Nrg4 in SC. In vitro, Nrg4 and UCP1 mRNA levels in adipocytes were dose- and time-dependently decreased under TNFα treatment. Conclusions Nrg4, UCP1, VEGF-A and CDH5 mRNA expression in adipose tissues display a depot-specific pattern. Nrg4 mRNA levels in adipose tissue are decreased with obesity and associated with WAT browning and angiogenesis. TNFα may be involved in the regulation of Nrg4 level in adipose tissue, which may be one of the causes of the down-regulation of Nrg4 expression in obesity with chronic inflammatory response.

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

IntroductionNeuregulin 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.MethodsObservational 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.ResultsSeven 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).ConclusionOur 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.

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. 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. 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. 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.

Elevated serum neuregulin 4 levels in patients with hyperthyroidism.

ObjectiveRecent studies have shown that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, plays an important role in the prevention of obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD). Considering that thyroid hormone (TH) has profound effects on whole-body energy metabolism, we speculate that circulating Nrg4 levels might be altered in patients with hyperthyroidism.Design and methodsA total of 129 hyperthyroid patients and 100 healthy subjects were recruited. Of them, 39 hyperthyroid patients received thionamide treatment for 3 months until euthyroidism. Serum Nrg4 levels were determined using the ELISA method. To further confirm the relationship between TH and Nrg4, C57BL/6 mice were treated with T3 and quantitative real-time PCR was performed to detect Nrg4 gene expression.ResultsSerum Nrg4 levels were significantly elevated in hyperthyroid patients as compared with normal controls (3.84 ± 1.63 vs 2.21 ± 1.04 ng/mL, P < 0.001). After achieving euthyroidism by thionamide treatment, serum Nrg4 levels dropped markedly from 3.57 ± 1.26 to 1.94 ± 0.72 ng/ml (P < 0.001). After adjustment for potential confounders, serum Nrg4 levels were independently associated with hyperthyroidism. The upregulation of Nrg4 expression in the livers and white adipose tissues by T3 was further confirmed by animal and cell culture experiments.ConclusionsSerum Nrg4 levels were increased in patients with hyperthyroidism. The liver and white adipose tissue might be primary sources contributing to elevated serum Nrg4 concentrations.

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 (β = -2.009, p = 0.048) and homeostasis model assessment of insulin resistance (β = -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.

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 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.

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 (β = 0.910, p < .001), glucose 2-h OGTT (β = 0.866, p < .001) and HOMA-IR (β = 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.

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.

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). 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. The nT2DM patients with the highest hs-CRP levels (>2.46mg/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 (<0.63mg/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. 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.