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

Abstract

Background: 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.

Aim: 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).

Methods: A search for relevant studies was performed systematically using prominent search engines, including PubMed, Google Scholar, and Embase, by following PRISMA guidelines.

Results: 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.

Conclusion: 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.

Keywords: Neuregulin 4; brown adipose tissue; cardiovascular diseases; diabetes mellitus; non-alcoholic fatty liver disease; obesity.

Figure 1.

A representative flow diagram showing preferred reporting items for systematic reviews and meta-analysis (PRISMA) for study inclusion, with descriptive analysis for searching, screening, and final selection.

Figure 2.

Putative model depicting the low circulating levels of neuregulin 4 (Nrg4) and its association with the markers of obesity and related metabolic diseases, including non-alcoholic diseases (NAFLD), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM), as well as cardiovascular diseases (CVD). BAT, brown adipose tissue; BMI, body mass index; CAD, coronary artery disease; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HbA1c, glycated hemoglobin A1c; hdl-c, high-density lipoprotein cholesterol; hs-crp, high-sensitivity C-reactive protein; HOMA-IR, homeostatic model assessment for insulin resistance; IL-6, interleukin 6; NAFLD, non-alcoholic diseases; MCP-1, monocyte chemoattractant protein-1, Nrg4, neuregulin 4; TC, total cholesterol; TG, triglyceride; tnf-α, tumor necrosis factor alpha; WC, waist circumference; WHtR, waist-height ratio.