Nrg4, a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, especially enriched in brown fat [2]. It plays a crucial role in maintaining metabolic homeostasis and is involved in multiple biological processes. Signaling pathways related to Nrg4 include Akt-nuclear factor-κB, ErbB3/ErbB4, AMPK/mTOR, and AMPK/NRF2, which are associated with its beneficial effects on various tissues [1,2,4,5].

In male mice, BAT-specific Nrg4 deficiency accelerates vascular inflammation, endothelial dysfunction, and atherosclerosis, while its restoration alleviates these conditions, revealing Nrg4 as a potential cross-talk factor between brown adipose tissue (BAT) and arteries in atherosclerosis [1]. In adipose tissue, Nrg4 expression is reduced in rodent and human obesity. Mice with gain-and loss-of-function of Nrg4 demonstrate its role in protecting against diet-induced insulin resistance and hepatic steatosis by attenuating hepatic lipogenic signaling [2]. In aged mice, delivery of recombinant NRG4 protein can ameliorate age-associated insulin resistance, glucose disorders, and other metabolic dysfunctions [3].

In summary, Nrg4 is a key factor in metabolic regulation and has a significant impact on multiple disease conditions. The use of gene knockout (KO) or conditional knockout (CKO) mouse models in these studies has revealed its role in atherosclerosis, obesity-associated disorders, age-associated metabolic dysfunction, among others, providing potential therapeutic targets for these diseases.

References:

1. Shi, Lingfeng, Li, Yixiang, Xu, Xiaoli, Xiang, Lingwei, Xiang, Guangda. 2022. Brown adipose tissue-derived Nrg4 alleviates endothelial inflammation and atherosclerosis in male mice. In Nature metabolism, 4, 1573-1590. doi:10.1038/s42255-022-00671-0. https://pubmed.ncbi.nlm.nih.gov/36400933/

2. Wang, Guo-Xiao, Zhao, Xu-Yun, Meng, Zhuo-Xian, Blüher, Matthias, Lin, Jiandie D. 2014. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. In Nature medicine, 20, 1436-1443. doi:10.1038/nm.3713. https://pubmed.ncbi.nlm.nih.gov/25401691/

3. Chen, Liwei, Xuan, Ye, Zhu, Yangyang, Jin, Li, Yu, Haoyong. 2024. Adipocyte secreted NRG4 ameliorates age-associated metabolic dysfunction. In Biochemical pharmacology, 225, 116327. doi:10.1016/j.bcp.2024.116327. https://pubmed.ncbi.nlm.nih.gov/38823457/

4. Wang, Hongchao, Wang, Lijie, Hu, Fuli, Li, Fang, Guo, Bingyan. 2022. Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway. In Cardiovascular diabetology, 21, 205. doi:10.1186/s12933-022-01643-0. https://pubmed.ncbi.nlm.nih.gov/36221104/

5. Wang, Pengfei, Guo, Xiaohua, Wang, Hongchao, Ma, Meifang, Guo, Bingyan. 2024. Neuregulin-4 protects cardiomyocytes against high-glucose-induced ferroptosis via the AMPK/NRF2 signalling pathway. In Biology direct, 19, 62. doi:10.1186/s13062-024-00505-x. https://pubmed.ncbi.nlm.nih.gov/39095871/