Metrnl, also known as Meteorin-like, Cometin, Subfatin, Interleukin-39, Interleukin-41, Meteorin-β, and Metrn-β/Metrnβ, is a widely-distributed secreted protein [5]. It is involved in regulating glucose and lipid metabolism, maintaining cardiovascular system homeostasis, and has pleiotropic effects on inflammation, immunology, and metabolism [3,4]. It activates different intracellular signaling pathways in various cell types, such as adipocytes, macrophages, myocytes, and cardiomyocytes [6].

In diabetic cardiomyopathy, cardiac-specific Metrnl overexpression ameliorated cardiac injury and dysfunction in both type 1 and type 2 diabetic mice, while specific deletion in the heart had the opposite phenotypes. Mechanistically, Metrnl activated the autophagy pathway and inhibited the cGAS/STING signaling in a LKB1/AMPK/ULK1-dependent mechanism [1]. In D-galactose-induced aging mice, Metrnl knockout did not affect baseline cognitive functions but aggravated cognitive impairment in aging mice and significantly reduced hippocampal BDNF, TrkB, and GFAP levels [2].

In conclusion, Metrnl plays crucial roles in multiple biological processes, especially in maintaining metabolic and cardiovascular homeostasis. The use of gene knockout (KO) and conditional knockout (CKO) mouse models has revealed its importance in diseases like diabetic cardiomyopathy and aging-related cognitive dysfunction, providing potential therapeutic targets for these conditions.