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 signaling pathways, such as the Akt-nuclear factor-κB, ErbB3/4, AMPK/mTOR, and AMPK/NRF2 signaling pathways [1,2,4,5]. Nrg4 is also associated with various physiological and pathological processes, including the regulation of vascular function, metabolism, and inflammation, making it a potential therapeutic target for many diseases [1-7,9,10]. Gene knockout (KO) and conditional knockout (CKO) mouse models have been valuable in studying its functions.

In BAT-specific Nrg4-deficient male mice, there is an acceleration of vascular inflammation, adhesion responses, endothelial dysfunction, apoptosis, and atherosclerosis, indicating that Nrg4 is crucial for maintaining vascular health [1]. Adipose tissue Nrg4 expression reduction in rodent obesity models, along with 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]. In aged mice, delivering recombinant NRG4 protein can ameliorate age-associated insulin resistance, glucose disorders, hepatic steatosis, and sarcopenia, suggesting its importance in age-related metabolic dysfunction [3].

In conclusion, Nrg4 is an important endocrine factor in adipose tissue, especially brown fat, with functions in maintaining metabolic homeostasis, protecting against age-associated metabolic dysfunction, and alleviating endothelial inflammation and atherosclerosis. The use of Nrg4 KO/CKO mouse models has significantly contributed to understanding its role in these disease-related processes, providing potential therapeutic directions for obesity-associated disorders, age-related metabolic diseases, and atherosclerosis [1-3].