Low circulating levels of neuregulin 4 as a potential biomarker associated with the severity and prognosis of obesity-related metabolic diseases: a systematic review

Neuregulin 4 (Nrg4) is a brown adipose tissue-derived adipokine that greatly affects systemic metabolism and improves metabolic derangements. Although abnormal circulating levels of Nrg4 are common in obesity, it remains elusive whether low or elevated levels of this batokine are associated with the onset of metabolic diseases. To assess Nrg4 levels and its role as a feasible biomarker to predict the severity of obesity, gestational diabetes mellitus (GDM), type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). A search for relevant studies was performed systematically using prominent search engines, including PubMed, Google Scholar, and Embase, by following PRISMA guidelines. Ample clinical evidence reported low serum/plasma levels of Nrg4 in obesity and these were inversely proportional to the indices of metabolic syndrome, including body mass index, waist circumference, triglycerides, fasting plasma glucose, and homoeostatic model assessment for insulin resistance as well as high-sensitivity C-reactive protein. Low circulating Nrg4 levels may aid in the prediction of morbid obesity, and subsequent GDM, T2DM, NAFLD, and CVD. Current clinical evidence emphasizes that the circulating levels of Nrg4 are decreased in morbid obesity, and it also highlights that Nrg4 May serve as a potential prognostic biomarker for obesity-related metabolic diseases.

神经调节蛋白4（Neuregulin 4, Nrg4）是一种棕色脂肪组织衍生的脂肪因子，可显著调控全身代谢并改善代谢紊乱。尽管肥胖人群常存在循环Nrg4水平异常，但该脂肪因子的水平降低或升高是否与代谢性疾病的发病相关，目前仍有待阐明。本研究旨在评估Nrg4的循环水平，以及其作为可行性生物标志物预测肥胖、妊娠糖尿病（gestational diabetes mellitus, GDM）、2型糖尿病（type 2 diabetes mellitus, T2DM）、非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）及心血管疾病（cardiovascular diseases, CVD）严重程度的应用价值。研究遵循系统评价与Meta分析优先报告条目（PRISMA）指南，通过PubMed、Google Scholar及Embase等主流学术搜索引擎开展系统性文献检索。现有大量临床证据显示，肥胖患者的血清/血浆Nrg4水平显著降低，且该水平与代谢综合征各项指标呈负相关，包括体重指数、腰围、甘油三酯、空腹血糖、胰岛素抵抗稳态模型评估指标及高敏C反应蛋白（high-sensitivity C-reactive protein, hs-CRP）。循环Nrg4水平降低或可辅助预测病态肥胖，以及后续发生的GDM、T2DM、NAFLD与CVD。当前临床证据均证实，病态肥胖患者的循环Nrg4水平降低，同时也凸显出Nrg4可作为肥胖相关代谢性疾病的潜在预后生物标志物。