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we seek to elucidate the function of mTORC1 signaling natural product libraries in the regulation of SREBP1c and fat metabolism in the liver. We find that mTORC1 activation is necessary for the induction of hepatic SREBP1c in response to feeding and insulin. We make an mTORC1 gain of function mouse model lacking TSC1 in the liver, to determine whether mTORC1 service is sufficient to generate hepatic lipogenesis. Despite our prediction, these mice are protected from both diet and age induced hepatic steatosis. In determining the system of this protection, we find that there's a surprising defect in the induction of SREBP1c in the livers of these mice stemming from the attenuation of hepatic Akt signaling. These studies suggest that mTORC1 activity an additional Akt driven pathway can be required and that alone cannot promote lipogenesis in the liver. Eventually, our data show the mTORC1 independent pathway downstream of Akt requires the reduction of a liverspecific isoform of INSIG. Insulin stimulates hepatic SREBP1c in an mTORC1 dependent way Since the mechanism of hepatic Chromoblastomycosis SREBP1c induction by insulin and Akt is badly understood, we wanted to ascertain whether mTORC1 action contributes to this induction in primary mouse hepatocytes. Insulin influences causing phosphorylation events on Akt resulting in subsequent phosphorylation of the Akt targets FOXO1, FOXO3a, and TSC2, the latter goal of that leads to mTORC1 activation and phosphorylation of S6K1. As described for other cell types, we realize that inhibition of mTORC1 with rapamycin enhances the insulin stimulated phosphorylation of Akt and its substrates in hepatocytes, presumably through inhibition of negative feedback systems. In a reaction to insulin, SREBP1c induces its expression, together with genes coding lipogenic enzymes, such as for instance FASN. Notably, despite enhancing Akt signaling, pre treatment with rapamycin suppressed Icotinib the capability of insulin to stimulate Fasn and Srebp1c. In comparison, mRNA expression of Igfbp1 and the gluconeogenic enzyme Pepck, two canonical FOXO1 goals, was inhibited by insulin however not affected by rapamycin. These findings are in keeping with those described lately for rat hepatocytes and show that mTORC1 is required for proper insulin stimulation of SREBP1c. Consistent with this impact on SREBP1c, rapamycin also significantly impairs the capability of insulin to promote de novo lipid synthesis in hepatocytes. To look for the meaning of the findings in vivo, we subjected mice to an overnight fast followed closely by refeeding. Giving initiates hepatic Akt and mTORC1 signaling and encourages the expression and control of SREBP1 and enhanced expression of its objectives. Significantly, SREBP1c activation was blocked by treatment with rapamycin before eating, without effects on goals.