In both models, GDC-0199 hepatic Akt2 has been shown to be the key mediator of lipid accumulation. Two weeks of rapamycin treatment significantly reduced mTORC1 activity but failed to suppress hepatic triglyceride levels in either model. Instead, there was a trend towards higher expression of lipogenic genes following rapamycin treatment. These observations led us to conclude that mTORC1 is neither necessary nor sufficient for steatosis. mTORC1 is a key effector downstream of Akt involved in cell growth and proliferation. Activation of either Akt or mTORC1 can lead to tumor formation. However, in the liver, these two kinases appear to have opposing effects on lipid accumulation. While the Pten-null livers developed profound steatosis, the Tsc1-null livers had low TG stores. This phenotypic difference correlated closely with their SB431542 relative Akt and mTORC1 activities and suggested that the Tsc12/2 hepatocytes could be protected from steatosis due to the feedback suppression of Akt by mTORC1. In support of this, the Tsc12/2 livers were resistant to high-fat diet-induced steatosis, and treatment with rapamycin abolished this ��protection�� resulting in hepatic TG accumulation that was equivalent to that seen in the wild-type hepatocytes under high-fat diet condition. Further, rapamycin led to the inhibition of mTORC1 and S6K1 resulting in the de-repression of Akt. Moreover, steatosis can be induced in the Tsc12/2 hepatocytes with the expression of Myr-Akt. These observations highlight the strong association between the balance of Akt and mTORC1 activities and the development of steatosis. When Akt dominates over mTORC1, steatosis ensues, whereas when mTORC1 overshadows Akt, fat deposition is suppressed. Other models of Akt suppression in the liver also result in a reduction in TG accumulation along with glucose intolerance similar to that of the Tsc12/2 mice. Thus, inhibition of hepatic Akt activity by any number of mechanisms leads to total hepatic insulin resistance. On the contrary, increasing Akt function in hepatocytes by direct or indirect means promotes lipogenesis and steatosis. These findings support our conclusion that the protective effect of mTORC1 from diet-induced steatosis is mediated via the inhibition of Akt signaling and underscore the potential for targeting Akt pharmacologically in the treatment of steatosis. Rapamycin is commonly used as an immunosuppressant following renal transplant, and more recently, its analogs have gained FDA approval for use in human tumors such as renal cell carcinoma and subependymal giant cell astrocytoma. Reports of rapamycin-induced glucose intolerance and dyslipidemia are consistent with our observations. However, steatosis is not consistently associated with the use of rapamycin in humans. We reasoned that the degree of hepatic TG varies with the effects of rapamycin on Akt activity.