Gpat3 Knockout Attenuates Adipose Loss and Steatohepatitis in Agpat2-Deficient Mice.

Congenital generalized lipodystrophy (CGL) type 1, caused by mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), is characterized by near-total absence of adipose tissue and severe metabolic disturbances, including hepatic steatosis, insulin resistance, and hypertriglyceridemia. Although AGPAT2's enzymatic function in lysophosphatidic acid acylation during glycerolipid biosynthesis is well characterized, the molecular mechanisms driving disease pathogenesis remain incompletely understood. In this study, significant up-regulation of glycerol-3-phosphate acyltransferase 3 (GPAT3), in both embryonic fibroblasts and liver tissue from AGPAT2-deficient mice, was identified. Through generation of Agpat2/Gpat3 double-knockout mice, it was demonstrated that GPAT3 ablation leads to multiple metabolic improvements: enhanced survival rates, partial preservation of adipose tissue (with more pronounced effects in brown than white adipose depots), marked attenuation of hepatic steatosis accompanied by reduced inflammation and fibrosis, and amelioration of hyperglycemia and hyperinsulinemia. Neonatal analyses demonstrated that GPAT3 deletion delayed adipose tissue degeneration while markedly decreasing macrophage infiltration (F4/80+ cells) and apoptotic signaling (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells). Ultrastructural examination revealed improved adipocyte morphology with normalized organelle architecture. These results identify GPAT3 as a key metabolic regulator in AGPAT2 deficiency, demonstrating that its inhibition partially restores adipose tissue and liver function. The conserved benefits of GPAT3 deficiency in both CGL1/AGPAT2 and CGL2/Seipin models highlight GPAT3 as a promising therapeutic target for congenital lipodystrophies.