The liver responds to insulin by blocking gluconeogenesis and stimulating lipogenesis. Insulin-induced lipid synthesis requires induction of the transcription factor SREBP1c, which is mediated by the activation of mTORC1 (mammalian target of rapamycin complex 1), through the Akt-dependent inhibition of the TSC1–TSC2 (tuberous sclerosis protein 1 and 2) complex. Yecies et al. now identify an mTORC1-independent pathway that induces SREBP1c to promote lipogenesis in the liver (Cell Metab. 14, 21–32; 2011).

To elucidate the role of mTORC1 in the regulation of hepatic lipid metabolism, Yecies et al. genetically ablated Tsc1 to generate a liver-specific, insulin-independent mTORC1 gain-of-function model (LTsc1KO). Surprisingly, rather than increase lipid accumulation, sustained mTORC1 activity protected the mice from liver steatosis. This was due to decreased hepatic SREBP1c expression and impaired lipogenic gene expression, indicating that mTORC1-independent mechanisms were also required for SREBP1c induction and lipogenesis.

The LTsc1KO mouse phenotype is similar to that of liver-specific Akt2 knockout mice and indeed LTsc1KO hepatocytes exhibited reduced Akt2 activity, consistent with reports that mTORC1 inhibits the insulin-Akt response through negative-feedback mechanisms. The authors established the importance of Akt in this context, by rescuing the lipogenic defect of LTsc1KO hepatocytes with constitutively active Akt2, and showed that in hepatocytes Akt2 represses INSIG2, an inhibitor of SREBP1c induction. These data uncover an mTORC1- independent mechanism for Akt-mediated regulation of liver lipogenesis.