Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine

Andrew L. Cangelosi; Anna M. Puszynska; Justin M. Roberts; Andrea Armani; Thao P. Nguyen; Jessica B. Spinelli; Tenzin Kunchok; Brianna Wang; Sze Ham Chan; Caroline A. Lewis; William C. Comb; George W. Bell; Aharon Helman; David M. Sabatini

doi:10.1126/science.abi9547

Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine

Andrew L. Cangelosi^*, Anna M. Puszynska, Justin M. Roberts, Andrea Armani, Thao P. Nguyen, Jessica B. Spinelli, Tenzin Kunchok, Brianna Wang, Sze Ham Chan, Caroline A. Lewis, William C. Comb, George W. Bell, Aharon Helman, David M. Sabatini

^*Corresponding author for this work

Institute of Biochemistry, Food Science and Nutrition

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through the leucine-binding Sestrin proteins, but the physiological functions and distribution of Sestrin-mediated leucine sensing in mammals are unknown. We find that mice lacking Sestrin1 and Sestrin2 cannot inhibit mTORC1 upon dietary leucine deprivation and suffer a rapid loss of white adipose tissue (WAT) and muscle. The WAT loss is driven by aberrant mTORC1 activity and fibroblast growth factor 21 (FGF21) production in the liver. Sestrin expression in the liver lobule is zonated, accounting for zone-specific regulation of mTORC1 activity and FGF21 induction by leucine. These results establish the mammalian Sestrins as physiological leucine sensors and reveal a spatial organization to nutrient sensing by the mTORC1 pathway.

Original language	English
Pages (from-to)	47-56
Number of pages	10
Journal	Science
Volume	377
Issue number	6601
DOIs	https://doi.org/10.1126/science.abi9547
State	Published - 1 Jul 2022

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Cangelosi, A. L., Puszynska, A. M., Roberts, J. M., Armani, A., Nguyen, T. P., Spinelli, J. B., Kunchok, T., Wang, B., Chan, S. H., Lewis, C. A., Comb, W. C., Bell, G. W., Helman, A., & Sabatini, D. M. (2022). Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine. Science, 377(6601), 47-56. https://doi.org/10.1126/science.abi9547

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title = "Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine",

abstract = "The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through the leucine-binding Sestrin proteins, but the physiological functions and distribution of Sestrin-mediated leucine sensing in mammals are unknown. We find that mice lacking Sestrin1 and Sestrin2 cannot inhibit mTORC1 upon dietary leucine deprivation and suffer a rapid loss of white adipose tissue (WAT) and muscle. The WAT loss is driven by aberrant mTORC1 activity and fibroblast growth factor 21 (FGF21) production in the liver. Sestrin expression in the liver lobule is zonated, accounting for zone-specific regulation of mTORC1 activity and FGF21 induction by leucine. These results establish the mammalian Sestrins as physiological leucine sensors and reveal a spatial organization to nutrient sensing by the mTORC1 pathway.",

author = "Cangelosi, {Andrew L.} and Puszynska, {Anna M.} and Roberts, {Justin M.} and Andrea Armani and Nguyen, {Thao P.} and Spinelli, {Jessica B.} and Tenzin Kunchok and Brianna Wang and Chan, {Sze Ham} and Lewis, {Caroline A.} and Comb, {William C.} and Bell, {George W.} and Aharon Helman and Sabatini, {David M.}",

note = "Publisher Copyright: {\textcopyright} 2022 the authors, some rights reserved",

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month = jul,

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doi = "10.1126/science.abi9547",

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AU - Cangelosi, Andrew L.

AU - Puszynska, Anna M.

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AU - Armani, Andrea

AU - Nguyen, Thao P.

AU - Spinelli, Jessica B.

AU - Kunchok, Tenzin

AU - Wang, Brianna

AU - Chan, Sze Ham

AU - Lewis, Caroline A.

AU - Comb, William C.

AU - Bell, George W.

AU - Helman, Aharon

AU - Sabatini, David M.

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AB - The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through the leucine-binding Sestrin proteins, but the physiological functions and distribution of Sestrin-mediated leucine sensing in mammals are unknown. We find that mice lacking Sestrin1 and Sestrin2 cannot inhibit mTORC1 upon dietary leucine deprivation and suffer a rapid loss of white adipose tissue (WAT) and muscle. The WAT loss is driven by aberrant mTORC1 activity and fibroblast growth factor 21 (FGF21) production in the liver. Sestrin expression in the liver lobule is zonated, accounting for zone-specific regulation of mTORC1 activity and FGF21 induction by leucine. These results establish the mammalian Sestrins as physiological leucine sensors and reveal a spatial organization to nutrient sensing by the mTORC1 pathway.

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Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine

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