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

Autoři: Yao Wang aff001;  Shuai Huang aff001;  Pei Yu aff001
Působiště autorů: NHC Key Laboratory of Hormones and Development (Tianjn Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjn Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China aff001
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article



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.


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.


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).


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.

Klíčová slova:

Brown adipose tissue – Cross-sectional studies – Glucose metabolism – Metabolic syndrome – Obesity


1. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006; 116: 1784–92. doi: 10.1172/JCI29126 16823476

2. Trujillo ME, Scherer PE. Adipose tissue-derived factors: impact onhealth and disease. Endocr Rev. 2006; 27: 762–78. doi: 10.1210/er.2006-0033 17056740

3. Waki H, Tontonoz P. Endocrine functions of adipose tissue. Annu Rev Pathol. 2007; 2: 31–56 doi: 10.1146/annurev.pathol.2.010506.091859 18039092

4. Parimisetty A, Dorsemans AC, Awada R, Ravanan P, Diotel N, Lefebvre d’Hellencourt C. Secret talk between adipose tissue and central nervous system via secreted factors-an emerging frontier in the neurodegenerative research. J. Neuroinflammation. 2016;13(1): 67. doi: 10.1186/s12974-016-0530-x 27012931

5. Cannon B, Nedergaard J. Brown adipose tissue: Function and physiological significance. Physiol. Rev. 2004; 84(1):277–359. doi: 10.1152/physrev.00015.2003 14715917

6. Wang GX, Zhao XY, Lin JD. The brown fat secretome: Metabolic functions beyond thermogenesis. Trends. Endocrin. Met. 2015; 26(5):231–37.

7. Villarroya F, Giralt M. The beneficial effects of brown fat transplantation: Further evidence of an endocrine role of brown adipose tissue. Endocrinology. 2015;156(7):2368–70. doi: 10.1210/en.2015-1423 26091427

8. Villarroya F, Cereijo R, Villarroya J, Giralt M. Brown adipose tissue as a secretory organ. Nat. Rev. Endocrinol. 2017; 13(1): 26–35. doi: 10.1038/nrendo.2016.136 27616452

9. Wang GX, Zhao XY, Meng ZX, Kern M, Dietrich A, Chen Z, et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nature medicine. 2014; 20(12):1436–43. doi: 10.1038/nm.3713 25401691

10. Pfeifer A. NRG4: an endocrine link between brown adipose tissue and liver. Cell Metab. 2015; 21:13–4. doi: 10.1016/j.cmet.2014.12.008 25565202

11. Ma Y, Gao M, Liu D. Preventing high fat diet-induced obesity and improving insulin sensitivity through neuregulin 4 gene transfer. Sci. Rep. 2016;6:26242. doi: 10.1038/srep26242 27184920

12. Wang W, Zhang Y, Yang C, Wang Y, Shen J, Shi M, et al. Feature Article: Transplantation of neuregulin 4-overexpressing adipose-derived mesenchymal stem cells ameliorates insulin resistance by attenuating hepatic steatosis. Exp Biol Med (Maywood). 2019; 244(7):565–578.

13. Rosell M, Kaforou M, Frontini A, Okolo A, Chan YW, Nikolopoulou E et al. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am J Physiol Endocrinol Metab. 2014; 306(8): 945–64.

14. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000; 283(15): 2008–12. doi: 10.1001/jama.283.15.2008 10789670

15. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat. Med. 2002; 21:1539–58. doi: 10.1002/sim.1186 12111919

16. Rupinski MT, Dunlap WP. Approximating pearson product-moment correlations from Kennall’s tau and Spearman’s rho. Educ. Psychol. Measur. 1996; 56: 419–29.

17. Wilson DB, Lipsey MW. The role of method in treatment effectiveness research: evidence from meta-analysis. Psychol Methods. 2001; 6(4): 413–29. 11778681

18. Wells G, Shea B, O’Connell J, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis. [updated 2011].

19. Rostom A, Dubé C, Cranney A, Saloojee N, Sy R, Garritty C, et al. Celiac Disease. Rockville (MD): Agency for Healthcare Research and Quality (US); 2004. (Evidence Reports/Technology Assessments, No.104.) Appendix D. Quality Assessment Forms.

20. Cai C, Lin M, Xu Y, Li X, Yang S, Zhang H. Association of circulating neuregulin 4 with metabolic syndrome in obese adults: a cross-sectional study. BMC Med. 2016;14(1):165. doi: 10.1186/s12916-016-0703-6 27772531

21. Chen LL, Peng MM, Zhang JY, Hu X, Min J, Huang QL, et al. Elevated circulating neuregulin4 level in patients with diabetes. Diabetes Metab. Res. Rev. 2016; 33: 2870.

22. Jiang J, Lin M, Xu Y, Shao J, Li X, Zhang H, et al. Circulating neuregulin 4 levels are inversely associated with subclinical cardiovascular disease in obese adults. Sci. Rep. 2016; 6: 36710. doi: 10.1038/srep36710 27819316

23. Kang YE, Kim JM, Choung S, Joung KH, Lee JH, Kim HJ, et al. Comparison of circulating Neuregulin 4 (Nrg4) levels in adults with newly diagnosed type 2 diabetes mellitus and controls without diabetes. Diabetes Res. Clin. Pract. 2016;117:1–3. doi: 10.1016/j.diabres.2016.04.007 27329015

24. Kurek Eken M, Yayla Abide C, Sahin Ersoy G, Altun Ensari T, Pekin O, Cevik O. Clinical significance of neuregulin 4 (NRG4) in gestational diabetes mellitus. Gynecol Endocrinol. 2018; 34(7): 605–8. doi: 10.1080/09513590.2017.1420772 29282998

25. Kralisch S, Hoffmann A, Kratzsch J, Blüher M, Blüher M, Stumvoll M, Fasshauer M, et al. The brown-fat-secreted adipokine neuregulin 4 is decreased in gestational diabetes mellitus. Diabetes Metab. 2018; 44(2):150–54. doi: 10.1016/j.diabet.2017.06.001 28709749

26. Zhang L, Fu Y, Zhou N, Cheng X, Chen C. Circulating neuregulin 4 concentrations in patients with newly diagnosed type 2 diabetes: a cross-sectional study. Endocrine. 2017; 57(3): 535–38. doi: 10.1007/s12020-017-1324-3 28523627

27. Oelkrug R, Polymeropoulos ET, Jastroch M. Brown adipose tissue: physiological function and evolutionary significance. J Comp Physiol B. 2015;185(6): 587–606. doi: 10.1007/s00360-015-0907-7 25966796

28. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17(2): 200–5. doi: 10.1038/nm.2297 21258337

29. Harari D, Tzahar E, Romano J, Shelly M, Pierce JH, Andrews GC, et al. Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene. 1999;18(17):2681–9. doi: 10.1038/sj.onc.1202631 10348342

30. Hayes NV, Blackburn E, Boyle MM, Russell GA, Frost TM, Morgan BJ, et al. Expression of neuregulin 4 splice variants in normal human tissues and prostate cancer and their effects on cell motility. Endocr Relat Cancer. 2011;18(1):39–49 20959441

31. Rosell M, Kaforou M, Frontini A, Okolo A, Chan YW, Nikolopoulou E, et al. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am. J. Physiol. Endocrinol. Metab. 2014; 306(8): 945–64.

32. Hayes NV, Newsam RJ, Baines AJ, Gullick WJ. Characterization of the cell membrane-associated products of the Neuregulin 4 gene. Oncogene. 2008; 27:715–20. doi: 10.1038/sj.onc.1210689 17684490

33. Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol. 2009; 218:460–6. doi: 10.1002/jcp.21635 19006176

34. South JC, Blackburn E, Brown IR, Gullick WJ. The neuregulin system of ligands and their receptors in rat islets of langerhans. Endocrinology. 2013;154:2385–92. doi: 10.1210/en.2012-2133 23610133

35. Dai YN, Zhu JZ, Fang ZY, Zhao DJ, Wan XY, Zhu HT, et al. A case-control study: association between circulating neuregulin 4 level and non-alcoholic fatty liver disease. Metab. 2015;64(12):1667–73.

Článek vyšel v časopise


2019 Číslo 12
Nejčtenější tento týden