1892-P: Hepatic Agpat5 Regulates Plasma Insulin in Obesity

There is increasing need to understand the molecular mechanisms contributing to obesity and type 2 diabetes. Agpat5, 1-acylglycerol-3-phosphate O-acyltransferase 5, is a lipid acyltransferase that esterifies the SN2 position of lysophospholipids to produce phospholipids. We previously identified Agpat5 within a genome-wide significant quantitative trait locus (QTL) associated with plasma insulin levels after high fat feeding in a mouse genetic reference population. We validated the effect of Agpat5, showing in multiple mouse models that treatment with Agpat5 antisense oligonucleotide (ASO) reduces plasma insulin after high-fat feeding. To investigate the hepatic role of Agpat5, we developed a liver-specific Agpat5 knockout mouse model. After 12 weeks of high-fat feeding, liver-specific Agpat5 knockout mice have significantly reduced fasting plasma insulin relative to control mice. Additionally, liver-specific Agpat5 knockout mice have significantly reduced hepatic triglycerides and are protected from hepatic steatosis. Investigating the effect of Agpat5 on hepatic insulin resistance, we found that loss of Agpat5 improves insulin signaling and reduces Foxo1 protein levels. Our studies suggest that hepatic Agpat5 may serve as a link between lipid metabolism and insulin signaling to regulate plasma insulin in obesity. Thus, drug therapies targeting Agpat5 could be developed to treat type 2 diabetes in obese populations.