The Lin28/let-7 axis regulates glucose metabolism

Soumya Raychaudhuri; Hao Zhu; Shyh Chang Ng; Ayellet V. Segr; Gen Shinoda; Samar P. Shah; William S. Einhorn; Ayumu Takeuchi; Jesse M. Engreitz; John P. Hagan; Michael G. Kharas; Achia Urbach; James E. Thornton; Robinson Triboulet; Richard I. Gregory; David Altshuler; George Q. Daley

doi:10.1016/j.cell.2011.08.033

The Lin28/let-7 axis regulates glucose metabolism

Soumya Raychaudhuri, Hao Zhu, Shyh Chang Ng, Ayellet V. Segr, Gen Shinoda, Samar P. Shah, William S. Einhorn, Ayumu Takeuchi, Jesse M. Engreitz, John P. Hagan, Michael G. Kharas, Achia Urbach, James E. Thornton, Robinson Triboulet, Richard I. Gregory, David Altshuler, George Q. Daley

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

Abstract

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. © 2011 Elsevier Inc.

Original language	English
Pages (from-to)	81-94
Number of pages	13
Journal	Cell
Volume	147
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2011.08.033
Publication status	Published - 30 Sept 2011

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@article{b01f1a1e95f9435b8ec75e757461e5c8,

title = "The Lin28/let-7 axis regulates glucose metabolism",

abstract = "The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. {\textcopyright} 2011 Elsevier Inc.",

author = "Soumya Raychaudhuri and Hao Zhu and Ng, {Shyh Chang} and Segr, {Ayellet V.} and Gen Shinoda and Shah, {Samar P.} and Einhorn, {William S.} and Ayumu Takeuchi and Engreitz, {Jesse M.} and Hagan, {John P.} and Kharas, {Michael G.} and Achia Urbach and Thornton, {James E.} and Robinson Triboulet and Gregory, {Richard I.} and David Altshuler and Daley, {George Q.}",

note = "R01 DK070055, NIDDK NIH HHS, United StatesT32 CA009172, NCI NIH HHS, United States, Howard Hughes Medical Institute, United States, Howard Hughes Medical Institute, United States",

year = "2011",

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doi = "10.1016/j.cell.2011.08.033",

language = "English",

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journal = "Cell",

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T1 - The Lin28/let-7 axis regulates glucose metabolism

AU - Raychaudhuri, Soumya

AU - Zhu, Hao

AU - Ng, Shyh Chang

AU - Segr, Ayellet V.

AU - Shinoda, Gen

AU - Shah, Samar P.

AU - Einhorn, William S.

AU - Takeuchi, Ayumu

AU - Engreitz, Jesse M.

AU - Hagan, John P.

AU - Kharas, Michael G.

AU - Urbach, Achia

AU - Thornton, James E.

AU - Triboulet, Robinson

AU - Gregory, Richard I.

AU - Altshuler, David

AU - Daley, George Q.

N1 - R01 DK070055, NIDDK NIH HHS, United StatesT32 CA009172, NCI NIH HHS, United States, Howard Hughes Medical Institute, United States, Howard Hughes Medical Institute, United States

PY - 2011/9/30

Y1 - 2011/9/30

N2 - The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. © 2011 Elsevier Inc.

AB - The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. © 2011 Elsevier Inc.

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DO - 10.1016/j.cell.2011.08.033

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SN - 1097-4172

VL - 147

SP - 81

EP - 94

JO - Cell

JF - Cell

IS - 1

ER -

The Lin28/let-7 axis regulates glucose metabolism

Abstract

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