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1-acylglycerol-3-phosphate-O-acyltransferase 1 (AGPAT1) is a ubiquitously expressed enzyme that catalyzes the formation of phosphatidic acid from lysophosphatidic acid. In turn, phosphatidic acid has been shown to increase mTOR activity, which is known to impair insulin signaling. This study was designed to determine whether AGPAT1 interacts with mTOR to alter insulin signaling. Overexpression of AGPAT1 in C2C12 cells and 3T3 preadipocytes increased the phosphorylation of p70S6K1 at Thr389; a downstream marker of mTOR activation. Importantly, increased p70S6K1 phosphorylation was accompanied by a decrease in the overall abundance of IRS-1 protein. There was also a decrease in the phosphorylation of Akt in AGPAT1 overexpressing cells. These effects were enhanced by the addition of fatty acids to the media. In humans, an overnight lipid infusion reduced insulin sensitivity and their skeletal muscle showed a 1.6-fold increase in AGPAT1 mRNA (p<0.05; n=7). Similarly, in liver samples from insulin resistant human subjects with NAFLD (non alcoholic fatty liver disease) there was an increase in AGPAT1 mRNA levels, which directly correlated with BMI (p<0.05). Overall these data indicate that AGPAT1 overexpression can lead to mTOR activation, which results in a down regulation of insulin signaling. The increase in AGPAT1 levels in human subjects with insulin resistance suggests that AGPAT1 may play a role in the development of insulin resistance. [ABSTRACT FROM AUTHOR]