Ubiquitin-Specific Protease 2 (USP2) as a Modulator of Energy Metabolism: A Review of Studies Using Animal and Cellular Models

Ubiquitin-specific protease 2 (USP2) is a deubiquitinase that controls various cellular events, including cell cycle progression and tumorigenesis. Along with cell culture models, mouse models induced using chemical blockers and gene engineering have substantially contributed to our knowledge of the crucial roles of USP2 in energy metabolism and metabolic disorders. This review summarizes the evidence of the role of USP2 in regulating energy metabolism in mice and cells under physiological and pathological conditions. In hepatocytes, a short isoform of USP2, USP2b, aggravates type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. Meanwhile, a long isoform of USP2 in adipose tissue macrophages, USP2a, attenuates the onset of diabetes. USP2a mitigates insulin resistance and subsequent muscle atrophy. In ventromedial hypothalamic neurons, USP2b inhibits an increase in blood glucose by repressing hepatic glycogenolysis. In addition to regulating diabetes, USP2 isoforms potentially regulate the progression of atherosclerosis by modulating macrophages and hepatocytes. In brown adipose tissue, USP2a regulates thermogenesis, thus influencing systemic energy control. Meanwhile, in testicular macrophages, USP2 protects the mitochondrial respiration of sperm and consequently contributes to maintaining the quality of frozen sperm for use in the treatment of male infertility. As USP2 is distributed to multiple cellular components, it mediates the polyubiquitination of various molecules. For instance, USP2 modulates the stability of various transcription regulators, including C/EBP-α, PPARγ, EBF2, and PGC1α. The accumulating evidence indicates that USP2 functions as a modulatory molecule for energy metabolism across organs.