TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

Cheoljun Choi; Yeonho Son; Jinyoung Kim; Yoon Keun Cho; Abhirup Saha; Minsu Kim; Hyeonyeong Im; Kyungmin Kim; Juhyeong Han; Jung Weon Lee; Je Kyung Seong; Yun Hee Lee

doi:10.2337/DB21-0145

TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

Cheoljun Choi, Yeonho Son, Jinyoung Kim, Yoon Keun Cho, Abhirup Saha, Minsu Kim, Hyeonyeong Im, Kyungmin Kim, Juhyeong Han, Jung Weon Lee, Je Kyung Seong, Yun Hee Lee

Department of Pharmacy

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

6 Citations (Scopus)

Abstract

Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adi-pocytes remains unclear. In this study we aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling–mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA sequencing analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in perox-isome proliferator–activated receptor a signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, the results of our study demonstrate that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggest that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.

Original language	English
Pages (from-to)	2000-2013
Number of pages	14
Journal	Diabetes
Volume	70
Issue number	9
DOIs	https://doi.org/10.2337/DB21-0145
Publication status	Published - 2021 Sept

Bibliographical note

Funding Information:
Funding. This research was supported by National Research Foundation of Korea grants (NRF-2019R1C1C1002014, NRF-2018R1A5A2024425, NRF-2013M3A9D5072550) funded by the Korean government (Ministry of Science and ICT). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. Y.-H.L. conceived and designed the study. C.C., Y.S., J.K., Y.K.C., A.S., M.K., H.I., K.K., J.H., J.W.L., and J.K.S. conducted the animal experiments. C.C. and Y.S. performed in vitro experiments. J.W.L. supplied the TSAHC reagent. C.C. and Y.-H.L. wrote the manuscript. All authors reviewed the manuscript. Y.-H.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Publisher Copyright:
© 2021 by the American Diabetes Association.

All Science Journal Classification (ASJC) codes

Internal Medicine
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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@article{5d92a4ea357748a1ab8ebf3f4730927d,

title = "TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue",

abstract = "Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adi-pocytes remains unclear. In this study we aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling–mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA sequencing analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in perox-isome proliferator–activated receptor a signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, the results of our study demonstrate that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggest that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.",

author = "Cheoljun Choi and Yeonho Son and Jinyoung Kim and Cho, {Yoon Keun} and Abhirup Saha and Minsu Kim and Hyeonyeong Im and Kyungmin Kim and Juhyeong Han and Lee, {Jung Weon} and Seong, {Je Kyung} and Lee, {Yun Hee}",

note = "Funding Information: Funding. This research was supported by National Research Foundation of Korea grants (NRF-2019R1C1C1002014, NRF-2018R1A5A2024425, NRF-2013M3A9D5072550) funded by the Korean government (Ministry of Science and ICT). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. Y.-H.L. conceived and designed the study. C.C., Y.S., J.K., Y.K.C., A.S., M.K., H.I., K.K., J.H., J.W.L., and J.K.S. conducted the animal experiments. C.C. and Y.S. performed in vitro experiments. J.W.L. supplied the TSAHC reagent. C.C. and Y.-H.L. wrote the manuscript. All authors reviewed the manuscript. Y.-H.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2021 by the American Diabetes Association.",

year = "2021",

month = sep,

doi = "10.2337/DB21-0145",

language = "English",

volume = "70",

pages = "2000--2013",

journal = "Diabetes",

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publisher = "American Diabetes Association Inc.",

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T1 - TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

AU - Choi, Cheoljun

AU - Son, Yeonho

AU - Kim, Jinyoung

AU - Cho, Yoon Keun

AU - Saha, Abhirup

AU - Kim, Minsu

AU - Im, Hyeonyeong

AU - Kim, Kyungmin

AU - Han, Juhyeong

AU - Lee, Jung Weon

AU - Seong, Je Kyung

AU - Lee, Yun Hee

N1 - Funding Information: Funding. This research was supported by National Research Foundation of Korea grants (NRF-2019R1C1C1002014, NRF-2018R1A5A2024425, NRF-2013M3A9D5072550) funded by the Korean government (Ministry of Science and ICT). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. Y.-H.L. conceived and designed the study. C.C., Y.S., J.K., Y.K.C., A.S., M.K., H.I., K.K., J.H., J.W.L., and J.K.S. conducted the animal experiments. C.C. and Y.S. performed in vitro experiments. J.W.L. supplied the TSAHC reagent. C.C. and Y.-H.L. wrote the manuscript. All authors reviewed the manuscript. Y.-H.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: © 2021 by the American Diabetes Association.

PY - 2021/9

Y1 - 2021/9

N2 - Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adi-pocytes remains unclear. In this study we aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling–mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA sequencing analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in perox-isome proliferator–activated receptor a signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, the results of our study demonstrate that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggest that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.

AB - Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adi-pocytes remains unclear. In this study we aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling–mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA sequencing analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in perox-isome proliferator–activated receptor a signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, the results of our study demonstrate that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggest that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.

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SP - 2000

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JO - Diabetes

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ER -

TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

Abstract

Bibliographical note

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UN SDGs

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