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Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin

Vanessa Byles, Yann Cormerais, Krystle Kalafut, Victor Barrera, James E. Hughes Hallett, Shannan Ho Sui, John M. Asara, Christopher M. Adams, Gerta Hoxhaj, Issam Ben-Sahra, Brendan D. Manning
doi: https://doi.org/10.1101/2021.05.02.442369
Vanessa Byles
1Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Yann Cormerais
1Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Krystle Kalafut
1Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Victor Barrera
2Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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James E. Hughes Hallett
1Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Shannan Ho Sui
2Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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John M. Asara
3Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA
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Christopher M. Adams
4Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA
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Gerta Hoxhaj
1Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
5Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Issam Ben-Sahra
6Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
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Brendan D. Manning
1Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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  • For correspondence: bmanning@hsph.harvard.edu
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Abstract

Objective The mechanistic target of rapamycin complex 1 (mTORC1) is dynamically regulated by fasting and feeding cycles in the liver to promote protein and lipid synthesis while suppressing autophagy. However, beyond these functions, the metabolic response of the liver to feeding and insulin signaling orchestrated by mTORC1 remains poorly defined. Here, we determine whether ATF4, a stress responsive transcription factor recently found to be independently regulated by mTORC1 signaling in proliferating cells, is responsive to hepatic mTORC1 signaling to alter hepatocyte metabolism.

Methods ATF4 protein levels and expression of canonical gene targets were analyzed in the liver following fasting and physiological feeding in the presence or absence of the mTORC1 inhibitor rapamycin. Primary hepatocytes from wild-type or liver-specific Atf4 knockout (LAtf4KO) mice were used to characterize the effects of insulin-stimulated mTORC1-ATF4 function on hepatocyte gene expression and metabolism. Both unbiased steady-state metabolomics and stable-isotope tracing methods were employed to define mTORC1 and ATF4-dependent metabolic changes. RNA-sequencing was used to determine global changes in feeding-induced transcripts in the livers of wild-type versus LAtf4KO mice.

Results We demonstrate that ATF4 and its metabolic gene targets are stimulated by mTORC1 signaling in the liver in response to feeding and in a hepatocyte-intrinsic manner by insulin. While we demonstrate that de novo purine and pyrimidine synthesis is stimulated by insulin through mTORC1 signaling in primary hepatocytes, this regulation was independent of ATF4. Metabolomics and metabolite tracing studies revealed that insulin-mTORC1-ATF4 signaling stimulates pathways of non-essential amino acid synthesis in primary hepatocytes, including those of alanine, aspartate, methionine, and cysteine, but not serine.

Conclusion The results demonstrate that ATF4 is a novel metabolic effector of mTORC1 in liver, extending the molecular consequences of feeding and insulin-induced mTORC1 signaling in this key metabolic tissue to the control of amino acid metabolism.

Competing Interest Statement

BDM is a shareholder and scientific advisory board member of Navitor Pharmaceuticals. CMA is a shareholder, director and officer of Emmyon, Inc. All other authors declare no competing financial interests.

Footnotes

  • Disclosure of Interest: BDM is a shareholder and scientific advisory board member of Navitor Pharmaceuticals. CMA is a shareholder, director and officer of Emmyon, Inc. All other authors declare no competing financial interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 03, 2021.
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Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin
Vanessa Byles, Yann Cormerais, Krystle Kalafut, Victor Barrera, James E. Hughes Hallett, Shannan Ho Sui, John M. Asara, Christopher M. Adams, Gerta Hoxhaj, Issam Ben-Sahra, Brendan D. Manning
bioRxiv 2021.05.02.442369; doi: https://doi.org/10.1101/2021.05.02.442369
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Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin
Vanessa Byles, Yann Cormerais, Krystle Kalafut, Victor Barrera, James E. Hughes Hallett, Shannan Ho Sui, John M. Asara, Christopher M. Adams, Gerta Hoxhaj, Issam Ben-Sahra, Brendan D. Manning
bioRxiv 2021.05.02.442369; doi: https://doi.org/10.1101/2021.05.02.442369

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