Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion. / Chen, Liang; Chen, Qiaoli; Xie, Bingxian; Quan, Chao; Sheng, Yang; Zhu, Sangsang; Rong, Ping; Zhou, Shuilian; Sakamoto, Kei; MacKintosh, Carol; Wang, Hong Yu; Chen, Shuai.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 26, 2016, p. 7219-7224.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Chen, L, Chen, Q, Xie, B, Quan, C, Sheng, Y, Zhu, S, Rong, P, Zhou, S, Sakamoto, K, MacKintosh, C, Wang, HY & Chen, S 2016, 'Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 26, pp. 7219-7224. https://doi.org/10.1073/pnas.1600581113

APA

Chen, L., Chen, Q., Xie, B., Quan, C., Sheng, Y., Zhu, S., Rong, P., Zhou, S., Sakamoto, K., MacKintosh, C., Wang, H. Y., & Chen, S. (2016). Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion. Proceedings of the National Academy of Sciences of the United States of America, 113(26), 7219-7224. https://doi.org/10.1073/pnas.1600581113

Vancouver

Chen L, Chen Q, Xie B, Quan C, Sheng Y, Zhu S et al. Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(26):7219-7224. https://doi.org/10.1073/pnas.1600581113

Author

Chen, Liang ; Chen, Qiaoli ; Xie, Bingxian ; Quan, Chao ; Sheng, Yang ; Zhu, Sangsang ; Rong, Ping ; Zhou, Shuilian ; Sakamoto, Kei ; MacKintosh, Carol ; Wang, Hong Yu ; Chen, Shuai. / Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 26. pp. 7219-7224.

Bibtex

@article{295f41e19ae343349c040dbca2059df9,
title = "Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion",
abstract = "Tre-2/USP6, BUB2, cdc16 domain family member 1 (the TBC domain is the GTPase activating protein domain) (TBC1D1) is a Rab GTPase activating protein that is phosphorylated on Ser231 by the AMP-activated protein kinase (AMPK) in response to intracellular energy stress. However, the in vivo role and importance of this phosphorylation event remains unknown. To address this question, we generated a mouse model harboring a TBC1D1Ser231Ala knockin (KI) mutation and found that the KI mice developed obesity on a normal chow diet. Mechanistically, TBC1D1 is located on insulin-like growth factor 1 (IGF1) storage vesicles, and the KI mutation increases endocrinal and paracrinal/autocrinal IGF1 secretion in an Rab8a-dependent manner. Hypersecretion of IGF1 causes increased expression of lipogenic genes via activating the protein kinase B (PKB; also known as Akt)-mammalian target of rapamycin (mTOR) pathway in adipose tissues, which contributes to the development of obesity, diabetes, and hepatic steatosis as the KI mice age. Collectively, these findings demonstrate that the AMPK-TBC1D1 signaling nexus interacts with the PKB-mTOR pathway via IGF1 secretion, which consequently controls expression of lipogenic genes in the adipose tissue. These findings also have implications for drug discovery to combat obesity.",
keywords = "AMPK, Igf1 secretion, Obesity, Phosphorylation, TBC1D1",
author = "Liang Chen and Qiaoli Chen and Bingxian Xie and Chao Quan and Yang Sheng and Sangsang Zhu and Ping Rong and Shuilian Zhou and Kei Sakamoto and Carol MacKintosh and Wang, {Hong Yu} and Shuai Chen",
year = "2016",
doi = "10.1073/pnas.1600581113",
language = "English",
volume = "113",
pages = "7219--7224",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "26",

}

RIS

TY - JOUR

T1 - Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion

AU - Chen, Liang

AU - Chen, Qiaoli

AU - Xie, Bingxian

AU - Quan, Chao

AU - Sheng, Yang

AU - Zhu, Sangsang

AU - Rong, Ping

AU - Zhou, Shuilian

AU - Sakamoto, Kei

AU - MacKintosh, Carol

AU - Wang, Hong Yu

AU - Chen, Shuai

PY - 2016

Y1 - 2016

N2 - Tre-2/USP6, BUB2, cdc16 domain family member 1 (the TBC domain is the GTPase activating protein domain) (TBC1D1) is a Rab GTPase activating protein that is phosphorylated on Ser231 by the AMP-activated protein kinase (AMPK) in response to intracellular energy stress. However, the in vivo role and importance of this phosphorylation event remains unknown. To address this question, we generated a mouse model harboring a TBC1D1Ser231Ala knockin (KI) mutation and found that the KI mice developed obesity on a normal chow diet. Mechanistically, TBC1D1 is located on insulin-like growth factor 1 (IGF1) storage vesicles, and the KI mutation increases endocrinal and paracrinal/autocrinal IGF1 secretion in an Rab8a-dependent manner. Hypersecretion of IGF1 causes increased expression of lipogenic genes via activating the protein kinase B (PKB; also known as Akt)-mammalian target of rapamycin (mTOR) pathway in adipose tissues, which contributes to the development of obesity, diabetes, and hepatic steatosis as the KI mice age. Collectively, these findings demonstrate that the AMPK-TBC1D1 signaling nexus interacts with the PKB-mTOR pathway via IGF1 secretion, which consequently controls expression of lipogenic genes in the adipose tissue. These findings also have implications for drug discovery to combat obesity.

AB - Tre-2/USP6, BUB2, cdc16 domain family member 1 (the TBC domain is the GTPase activating protein domain) (TBC1D1) is a Rab GTPase activating protein that is phosphorylated on Ser231 by the AMP-activated protein kinase (AMPK) in response to intracellular energy stress. However, the in vivo role and importance of this phosphorylation event remains unknown. To address this question, we generated a mouse model harboring a TBC1D1Ser231Ala knockin (KI) mutation and found that the KI mice developed obesity on a normal chow diet. Mechanistically, TBC1D1 is located on insulin-like growth factor 1 (IGF1) storage vesicles, and the KI mutation increases endocrinal and paracrinal/autocrinal IGF1 secretion in an Rab8a-dependent manner. Hypersecretion of IGF1 causes increased expression of lipogenic genes via activating the protein kinase B (PKB; also known as Akt)-mammalian target of rapamycin (mTOR) pathway in adipose tissues, which contributes to the development of obesity, diabetes, and hepatic steatosis as the KI mice age. Collectively, these findings demonstrate that the AMPK-TBC1D1 signaling nexus interacts with the PKB-mTOR pathway via IGF1 secretion, which consequently controls expression of lipogenic genes in the adipose tissue. These findings also have implications for drug discovery to combat obesity.

KW - AMPK

KW - Igf1 secretion

KW - Obesity

KW - Phosphorylation

KW - TBC1D1

U2 - 10.1073/pnas.1600581113

DO - 10.1073/pnas.1600581113

M3 - Journal article

C2 - 27307439

AN - SCOPUS:84976518565

VL - 113

SP - 7219

EP - 7224

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 26

ER -

ID: 238745754