Identification of Akt-independent Regulation of Hepatic Lipogenesis by Mammalian Target of Rapamycin (mTOR) Complex 2

Mammalian target of rapamycin complex 2 (mTORC2) is a key activator of protein kinases that act downstream of insulin and growth factor signaling. Here we report that mice lacking the essential mTORC2 component rictor in liver (LrictorKO) are unable to respond normally to insulin. In response to insulin, LrictorKO mice failed to inhibit hepatic glucose output. LrictorKO mice also fail to develop hepatic steatosis on a high fat diet and manifest half-normal serum cholesterol levels. This is accompanied by lower levels of expression of SREBP-1c and SREBP-2 and genes of fatty acid and cholesterol biosynthesis. LrictorKO mice had defects in insulin-stimulated Akt Ser-473 and Thr-308 phosphorylation, leading to decreased phosphorylation of Akt substrates FoxO, GSK-3β, PRAS40, AS160, and Tsc2. LrictorKO mice also manifest defects in insulin-activated mTORC1 activity, evidenced by decreased S6 kinase and Lipin1 phosphorylation. Glucose intolerance and insulin resistance of LrictorKO mice could be fully rescued by hepatic expression of activated Akt2 or dominant negative FoxO1. However, in the absence of mTORC2, forced Akt2 activation was unable to drive hepatic lipogenesis. Thus, we have identified an Akt-independent relay from mTORC2 to hepatic lipogenesis that separates the effects of insulin on glucose and lipid metabolism. Background: mTORC2 is an insulin-stimulated kinase that activates kinases such as Akt. Results: Hepatic mTORC2 deletion increased glucose output dependent on Akt-FoxO and blocked lipogenesis that was not restored by activation of Akt-FoxO signaling. Conclusion: mTORC2-dependent factors other than Akt are critical for hepatic lipogenesis. Significance: Understanding signals separating hepatic glucose output from lipogenesis is crucial for effective diabetes treatment.