Nmrk1, also known as nicotinamide riboside kinase 1, is an essential enzyme in the utilization of nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+). NAD+ is a co-enzyme in redox reactions and a substrate for various enzyme families, and thus Nmrk1 is crucial for NAD+ biosynthesis. It is involved in pathways related to energy metabolism, such as glycolipid metabolism, and is important for maintaining normal physiological functions [1,2,3,4,5,6]. Genetic models, like knockout mice, are valuable for studying its functions.

In whole-body and pancreatic β-cell-specific Nrk1 knockout (KO) mice, high-fat feeding or aging led to glucose intolerance and compromised β-cell response to a glucose challenge, suggesting Nrk1 is important for maintaining glucose tolerance and pancreatic β-cell function in these conditions [4]. In whole-body and liver-specific Nrk1 KO mice, there was decreased gluconeogenic potential, impaired mitochondrial function, and upon high-fat feeding, they developed glucose intolerance, insulin resistance, and hepatosteatosis, indicating endogenous Nrk1-mediated NR metabolism is critical for sustaining hepatic NAD+ levels and preventing diet-induced metabolic damage [5]. Also, in a triple-negative breast cancer cell model, silencing of Nrk1 in resistant cells did not increase the toxicity of the NAMPT inhibitor FK866, excluding this pathway as a compensatory mechanism of NAD+ production [7].

In conclusion, Nrk1 plays a vital role in maintaining NAD+ levels, which is essential for normal energy metabolism, glucose tolerance, and pancreatic β-cell function. Gene knockout mouse models have significantly contributed to understanding Nrk1's role in diet-and age-induced metabolic disorders and in cancer-related metabolic adaptation [4,5,7].