Nrg4, a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, especially enriched in brown fat. It plays a crucial role in maintaining metabolic homeostasis and is involved in multiple biological processes. Nrg4 exerts its functions through signaling pathways such as Akt-nuclear factor-κB, ErbB3/4, and AMPK/mTOR [1,2,4].

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 BAT and arteries in atherosclerosis [1]. In adipose tissue, Nrg4 expression is reduced in rodent and human obesity. Gain-and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis by attenuating hepatic lipogenic signaling [2]. Delivery of recombinant NRG4 protein into aged mice can ameliorate age-associated insulin resistance, glucose disorders, and other metabolic dysfunctions [3].

In summary, Nrg4 is a key factor in maintaining metabolic homeostasis. Studies using gene knockout or conditional knockout mouse models have revealed its important roles in various disease conditions including atherosclerosis, obesity-associated disorders, age-associated metabolic dysfunction, and diabetic cardiomyopathy. These findings suggest that Nrg4 could be a potential therapeutic target for treating these diseases.