biostudies-literatureUnknownUehara KNovo NordiskNIDDK NIH HHSUniversity of PennsylvaniaNational Institutes of HealthIn response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Re-expression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis.The Journal of clinical investigatione173782https://www.ebi.ac.uk/biostudies/studies/S-EPMC10977990biostudies-literaturemTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b.PMC10977990F32 DK127843Cox Research FundP30 DK019525NNF18CC0034900F31 DK128876R01 DK114291R01-DK125497,UM1126194,F31-DK128876,R01-DK114291,F32-DK127843P30 DK050306R01 DK125497Coopersmith TNRader DJRabinowitz JDSantoleri DSakamoto KGarcia Whitlock AECreasy KTLee WDStefkovich MQuinn Iii WJBiswas DTitchenell PMUehara KfalsemTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b.In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Re-expression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis.2024-01-01T00:00:00Z2024 Jan2025-04-22T21:31:46.066Z2025-04-06T03:36:10.753ZS-EPMC109779903829008710.1172/JCI173782