Arginase 1 promotes hepatic lipogenesis by regulating ERK2/PPARγ signaling in a non-canonical manner.

Obesity and related metabolic disorders, including metabolic dysfunction-associated steatohepatitis (MASLD), have reached epidemic proportions worldwide. We unveil a previously unknown moonlighting role for arginase 1 (Arg1) in facilitating hepatic lipogenesis. Male mice lacking hepatic Arg1 exhibit diminished lipid accumulation in both liver and adipocytes, an effect mirrored in genetically- or diet-induced obesity models following Arg1 inhibitor treatment. Mechanistically, Arg1 competes with RSK2 and Elk1 for binding to the substrate-binding pocket of extracellular signal-regulated kinase 2 (ERK2) via its S-shaped motif, thereby enhancing ERK2 ubiquitination and degradation and upregulating the AKT/mTOR/PPARγ and Elk1/c-Fos/PPARγ cascades, ultimately augmenting lipogenesis. Peptides designed to mimic the ERK2 substrate-binding pocket disrupt the Arg1-ERK2 interaction and improve metabolic profiles in obesity and MASLD models. Our findings implicate Arg1 regulates hepatic lipid metabolism via its physical interaction with ERK2, highlighting the Arg1-ERK2 interaction as a promising therapeutic target for obesity and related metabolic disorders in male mice.