Hepatic Adipose Triglyceride Lipase (ATGL) regulates glucose tolerance but not hepatic insulin signaling

Adipose triglyceride lipase (ATGL) performs the first step in triglyceride (TAG) hydrolysis in multiple tissues. We have shown that mice lacking hepatic ATGL accumulate TAG triglyceride due to attenuated TAG hydrolytic activity. Since hepatic steatosis is tightly associated with insulin resistance, we investigated whether hepatic ATGL mediates glucose tolerance and hepatic insulin action. Interestingly, mice treated with an adenoviral delivered shRNA targeting ATGL exhibited lower fasting serum glucose concentrations. Additionally, when fed with high fat diet, ATGL knockdown blocked the increase in fasting serum insulin levels observed in control shRNA‐treated mice despite higher hepatic TAG content. Oral glucose tolerance test demonstrated that ATGL shRNA‐treated mice were more responsive to oral glucose load than control mice suggesting that silencing expression of ATGL confers enhanced glucose tolerance. Although ATGL shRNA‐treated mice were steatotic, acute insulin administration had no effect on phosphorylation of insulin signaling mediators including Akt and IRS‐1 compared to control mice. Taken together, these data suggest that ATGL knockdown in vivo dissociates hepatic steatosis from impairments in glucose tolerance and insulin signaling. This work was supported by a NIH grant (DK085008) to D.G.M.