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.

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.

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.

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.

Elevated circulating Neuregulin4 level in patients with diabetes.

BACKGROUND: Neuregulin4 (Nrg4) is a novel adipokine expressed in adipose tissues, enriched in brown adipose tissue, and able to improve whole-body metabolism in rodent, thus having the potential to treat obesity-associated disorders such as diabetes. However, the association between serum Nrg4 levels and diabetes risk in human remains unclear. This study was designed to examine circulating Nrg4 levels in subjects with different glucose tolerance status. METHODS: Age-, sex-, and body mass index-matched subjects (n = 310: 83 normal glucose tolerance [NGT], 129 prediabetes, and 96 diabetes) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study (Reaction study) were included. Serum Nrg4 was measured via enzyme-linked immunosorbent assay. Basic anthropometric parameters, fasting plasma glucose and 2-hours postload plasma glucose, hemoglobin A1c , and serum lipid profile were also measured. RESULTS: The serum Nrg4 levels were higher in patients with diabetes than those with NGT and prediabetes (diabetes: 396.8[65.9, 709.4], NGT: 80.1[0, 554.1], prediabetes: 168.0[32.9, 463.9] pg/mL [median (interquartile range), both P < 0.05]). The Nrg4 concentration was correlated with fasting plasma glucose. When the top versus bottom quartiles of serum Nrg4 concentrations were compared with adjustment for age and sex, an odds ratio of 3.005 was observed in diabetes prevalence, which persisted after adjusting other potential confounding variables. Other nonglucose parameters as body mass index; waist, hip, and neck circumferences; alanine aminotransferase; triglyceride; high-density lipoprotein; uric acid; and estimated glomerular filtration rate were also correlated with serum Nrg4 (P < 0.05). CONCLUSIONS: The circulating Nrg4 level is elevated in the prediabetic and diabetic patients compared to control and is an independent risk factor associated with diabetes.

Circulating neuregulin 4 levels are inversely associated with subclinical cardiovascular disease in obese adults.

Neuregulin 4 (Nrg4) has been identified as a new secreted adipokine that may protect against development of obesity and metabolic disorders. However, information is not available regarding the association between circulating Nrg4 and subclinical atherosclerosis in humans. We measured serum Nrg4 in 485 obese adult subjects (aged 40 years or older) who had the measurement of carotid intima-media thickness (CIMT) recruited from the community. Individuals with increased CIMT and carotid plaque had lower levels of circulating Nrg4 than controls (p < 0.05). The risks of increased CIMT and atherosclerotic plaque were significantly decreased by 28% and 31% [OR (95% CI): 0.72 (0.53-0.98) and 0.69 (0.50-0.96), respectively], adjusting for age, sex, current smoking, alcohol consumption, physical activity, BMI, systolic BP, fasting glucose, total cholesterol, HDL-c, HOMA-IR, and body fat. Importantly, individuals in the lowest quartile of serum Nrg4 were 3.70 times (p < 0.001) more likely to have increased CIMT and 2.06 times (p < 0.05) more likely to have atherosclerotic plaque than those in the highest quartile in multivariable logistic regression analyses. These findings suggest that circulating Nrg4 concentrations are inversely associated with subclinical atherosclerosis in obese adults, and indicating that circulating Nrg4 might play a role in identifying patients at high risk for CVD.

Association of circulating neuregulin 4 with metabolic syndrome in obese adults: a cross-sectional study.

BACKGROUND: Neuregulin 4 (Nrg4) is a secreted adipokine recently identified as playing an important role in modulating systemic energy metabolism and the development of obesity-associated disorders. However, information is not available regarding the association between circulating Nrg4 and risk of metabolic syndrome (MetS) in humans. METHODS: We measured serum Nrg4 in 1212 obese adult subjects (aged 40 years or older), with a waist circumference greater than 90 cm for men or 80 cm for women, recruited from the community. RESULTS: MetS subjects had lower levels of circulating Nrg4 than healthy controls (P < 0.01). The prevalence of MetS was higher in subjects with lower levels of circulating Nrg4 compared to those with higher values (67.3 % vs. 57.4 %, P < 0.05). Likewise, subjects with low levels of circulating Nrg4 had high prevalence of raised fasting glucose and blood pressure, but there was no association with raised triglycerides and reduced HDL-c. In multivariable logistic regression analyses, increased serum Nrg4 was significantly associated with reduced risk of MetS (OR: 0.603; 95 % CI, 0.439-0.828; P = 0.002), adjusting for age, gender, current smoking, alcohol consumption, physical activity, BMI, systolic blood pressure, fasting glucose, triglyceride, HDL-c, HOMA-IR, and body fat mass; however, such associations with serum Nrg4 were not noted for each component of MetS. CONCLUSIONS: These findings indicate that circulating Nrg4 concentrations are inversely associated with risk of MetS in obese Chinese adults, suggesting that circulating Nrg4 concentrations may be a protective factor in the development of MetS.

Circulating neuregulin during the transition from stage A to stage B/C heart failure in a breast cancer cohort.

BACKGROUND: Breast cancer (BC) treatments can cause heart failure (HF) in a subset of patients. ACC/AHA guidelines classify patients receiving cardiotoxic medications as stage A, a high-risk population for the development of HF. Circulating neuregulin (NRG) correlates with outcomes in stage C and D HF. We examined the levels of NRG in a BC cohort receiving cardiotoxic chemotherapy and its relationship with adverse cardiac effects during the transition from stage A to stage B or C HF. METHODS AND RESULTS: In an ongoing prospective study, a planned interim analysis of 78 BC women receiving either anthracycline (AC) or trastuzumab (Tsz) was performed. Biometric data, cardiac risk factors, and NRG levels, were collected before chemotherapy and after completion of AC therapy and/or 3 months into Tsz therapy. Cardiac function was measured by left ventricular ejection fraction (LVEF) by echocardiography at the above time points and longitudinally as standard of care. The interim cohort was predominately white with stage II BC and a median age of 50 years. A reduction of >10 absolute percentage points in LVEF was observed in 21.4% of the cohort, representing a transition from stage A to stage B or C HF. A statistically significant drop in plasma NRG was observed in women treated with AC and/or Tsz (P < .001). Additionally, baseline NRG correlated with the maximal change in LVEF. CONCLUSIONS: More than 20% of women experienced cardiac dysfunction, detected by decline in LVEF, and were reclassified as stage B or C HF. Plasma NRG levels were reduced after exposure to cardiotoxic chemotherapy, suggesting a loss in a cardioprotective growth factor. Higher baseline NRG levels were observed in those with the greatest decline in LVEF, supporting the continued investigation of NRG as a potential prognostic marker in early-stage HF.