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mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b
Kahealani Uehara, … , Joshua D. Rabinowitz, Paul M. Titchenell
Kahealani Uehara, … , Joshua D. Rabinowitz, Paul M. Titchenell
Published January 30, 2024
Citation Information: J Clin Invest. 2024;134(7):e173782. https://doi.org/10.1172/JCI173782.
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Research Article Endocrinology Metabolism

mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b

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Abstract

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.

Authors

Kahealani Uehara, Won Dong Lee, Megan Stefkovich, Dipsikha Biswas, Dominic Santoleri, Anna Garcia Whitlock, William Quinn III, Talia Coopersmith, Kate Townsend Creasy, Daniel J. Rader, Kei Sakamoto, Joshua D. Rabinowitz, Paul M. Titchenell

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Figure 1

Postprandial metabolomics reveal increased glycogen precursors in the absence of mTORC1 activity.

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Postprandial metabolomics reveal increased glycogen precursors in the ab...
(A–C) Mice aged 10 to 12 weeks were fasted for 16 hours (Fasted) then given food for 4 hours (Refed). (A) Heat map of differential metabolite abundance shown as log2 (FC) compared with fasted livers. (B) Volcano plot showing –log10(P value versus fasted) on y-axis and log2 (FC versus fasted) on x-axis. Blue dots represent log2 (FC) < –2, P < 0.01. Red dots represent llog2 (FC) > 2, and P < 0.01. (C) The relative abundance of selected glucose metabolites. (D–G) RptorloxP/loxP mice aged 10–12 weeks were injected with AAV8-TBG-Cre (L-Raptor-KO) or AAV8-TBG-GFP (Control). Two weeks after injection, mice were fasted overnight, then chow was reintroduced for 4 hours before sacrifice. (D) Immunoblot demonstrating loss of Raptor protein and inhibition of mTORC1 signaling. (E) Heat map of selected glucose metabolite relative abundance shown as log2 (FC) compared with control fed livers. (F) Hepatic glycogen in fed livers. Data shown as mean ± SEM. (G) PAS staining for glycogen (pink). Scale bar: 400 μm. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus WT fasted via student’s t test. Red indicates higher metabolite abundance.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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