Hyperinsulinemia in association with obesity is a key contributor to type 2 diabetes. Using a mouse genetic reference population, we identified Agpat5, 1-acylglycerol-3-phosphate O-acyltransferase 5, as a gene associated with plasma insulin levels after high fat feeding. Using a genetic interaction analysis, we also uncovered a relationship between Agpat5 and Foxo1, Forkhead Box O1. Agpat5 is an acyltransferase that produces diverse phospholipids by esterifying lysophospholipids. Foxo1 is an insulin responsive transcription factor. To biologically validate the role of Agpat5 in obesity associated hyperinsulinemia, we treated obese high fat fed mice with an antisense oligonucleotide (ASO) that targets Agpat5 to inhibit its gene expression. We show that Agpat5 ASO treated obese mice have significantly lower fed and fasting plasma insulin, as well as improved glucose tolerance and reduced Foxo1 protein. Analysis of insulin secretion and clearance indicates that Agpat5 ASO treated mice clear insulin more efficiently, as assessed by c-peptide to insulin ratio. To understand the tissue-specific roles of Agpat5 in obesity, we generated liver- and adipose- specific knockout mice. We show that hepatic Agpat5 promotes hepatic insulin resistance and hyperinsulinemia through a mechanism involving hepatic Foxo1. Furthermore, we show that adipose Agpat5 promotes hyperinsulinemia and adiposity. Our studies suggest that Agpat5 promotes hyperinsulinemia in obesity through regulation of Foxo1 signaling and insulin clearance.


S.L. St. Clair: None. S.L. Belisle: None. S. Bruggeman: None. F.B. Leyva Jaimes: None. B.A. Burgess: None. Z. Li: None. B. Parks: None.

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