mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b
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mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b. / Uehara, Kahealani; Lee, Won Dong; Stefkovich, Megan; Biswas, Dipsikha; Santoleri, Dominic; Whitlock, Anna Garcia; Quinn, William; Coopersmith, Talia; Creasy, Kate Townsend; Rader, Daniel J.; Sakamoto, Kei; Rabinowitz, Joshua D.; Titchenell, Paul M.
In: Journal of Clinical Investigation, Vol. 134, No. 7, e173782, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b
AU - Uehara, Kahealani
AU - Lee, Won Dong
AU - Stefkovich, Megan
AU - Biswas, Dipsikha
AU - Santoleri, Dominic
AU - Whitlock, Anna Garcia
AU - Quinn, William
AU - Coopersmith, Talia
AU - Creasy, Kate Townsend
AU - Rader, Daniel J.
AU - Sakamoto, Kei
AU - Rabinowitz, Joshua D.
AU - Titchenell, Paul M.
N1 - Publisher Copyright: © 2024, Uehara et al.
PY - 2024
Y1 - 2024
N2 - 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. Reexpression 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.
AB - 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. Reexpression 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.
U2 - 10.1172/JCI173782
DO - 10.1172/JCI173782
M3 - Journal article
C2 - 38290087
AN - SCOPUS:85189327032
VL - 134
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 7
M1 - e173782
ER -
ID: 389312405