In the present study, liver-specific PLIN2 knockout (PLIN2LKO) mice were fed a Western-type diet for 12 weeks to (1) evaluate the contributions of lipolysis and lipophagy to reductions in hepatic TAG following PLIN2 deficiency, as well as (2) to delineate the effect of hepatic PLIN2 loss, specifically, on the development of obesity and insulin resistance early in the progression of NAFLD. Here, PLIN2 is linked to metabolic dysfunction-associated steatotic liver disease.