Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16

Yusuke Nakatsu; Yasuka Matsunaga; Takeshi Yamamotoya; Koji Ueda; Masa ki Inoue; Yu Mizuno; Mikako Nakanishi; Tomomi Sano; Yosuke Yamawaki; Akifumi Kushiyama; Hideyuki Sakoda; Midori Fujishiro; Akihide Ryo; Hiraku Ono; Tohru Minamino; Shin Ichiro Takahashi; Haruya Ohno; Masayasu Yoneda; Kei Takahashi; Hisamitsu Ishihara; Hideki Katagiri; Fusanori Nishimura; Takashi Kanematsu; Tetsuya Yamada; Tomoichiro Asano

doi:10.1016/j.celrep.2019.02.066

Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16

Yusuke Nakatsu, Yasuka Matsunaga, Takeshi Yamamotoya, Koji Ueda, Masa ki Inoue, Yu Mizuno, Mikako Nakanishi, Tomomi Sano, Yosuke Yamawaki, Akifumi Kushiyama, Hideyuki Sakoda, Midori Fujishiro, Akihide Ryo, Hiraku Ono, Tohru Minamino, Shin Ichiro Takahashi, Haruya Ohno, Masayasu Yoneda, Kei Takahashi, Hisamitsu IshiharaHideki Katagiri, Fusanori Nishimura, Takashi Kanematsu, Tetsuya Yamada, Tomoichiro Asano

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Abstract

Non-shivering thermogenesis in adipocytes provides defense against low temperatures and obesity development, but the underlying regulatory mechanism remains to be fully clarified. Based on both markedly increased Pin1 expression in states of excess nutrition and resistance to obesity development in Pin1 null mice, we speculated that adipocyte Pin1 may play a role in thermogenic programs. Adipose-specific Pin1 knockout (adPin1 KO) mice showed enhanced transcription of thermogenic genes and tolerance to hypothermia when exposed to cold. In addition, adPin1 KO mice were resistant to high-fat diet-induced obesity and glucose intolerance. A series of experiments revealed that Pin1 binds to PRDM16 and thereby promotes its degradation through the ubiquitin-proteasome system. Consistent with these results, Pin1 deletion in differentiated adipocytes showed enhancement of thermogenic programs in response to the β3 agonist CL316243 through the upregulation of PRDM16 proteins. These observations indicate that Pin1 is a negative regulator of non-shivering thermogenesis.

Original language	English
Pages (from-to)	3221-3230.e3
Journal	Cell Reports
Volume	26
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2019.02.066
Publication status	Published - Mar 19 2019

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Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2019.02.066

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Nakatsu, Y., Matsunaga, Y., Yamamotoya, T., Ueda, K., Inoue, M. K., Mizuno, Y., Nakanishi, M., Sano, T., Yamawaki, Y., Kushiyama, A., Sakoda, H., Fujishiro, M., Ryo, A., Ono, H., Minamino, T., Takahashi, S. I., Ohno, H., Yoneda, M., Takahashi, K., ... Asano, T. (2019). Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. Cell Reports, 26(12), 3221-3230.e3. https://doi.org/10.1016/j.celrep.2019.02.066

Nakatsu, Y, Matsunaga, Y, Yamamotoya, T, Ueda, K, Inoue, MK, Mizuno, Y, Nakanishi, M, Sano, T, Yamawaki, Y, Kushiyama, A, Sakoda, H, Fujishiro, M, Ryo, A, Ono, H, Minamino, T, Takahashi, SI, Ohno, H, Yoneda, M, Takahashi, K, Ishihara, H, Katagiri, H, Nishimura, F , Kanematsu, T, Yamada, T & Asano, T 2019, 'Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16', Cell Reports, vol. 26, no. 12, pp. 3221-3230.e3. https://doi.org/10.1016/j.celrep.2019.02.066

@article{89e9043ade1e4f3baf79eb611e3356aa,

title = "Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16",

abstract = "Non-shivering thermogenesis in adipocytes provides defense against low temperatures and obesity development, but the underlying regulatory mechanism remains to be fully clarified. Based on both markedly increased Pin1 expression in states of excess nutrition and resistance to obesity development in Pin1 null mice, we speculated that adipocyte Pin1 may play a role in thermogenic programs. Adipose-specific Pin1 knockout (adPin1 KO) mice showed enhanced transcription of thermogenic genes and tolerance to hypothermia when exposed to cold. In addition, adPin1 KO mice were resistant to high-fat diet-induced obesity and glucose intolerance. A series of experiments revealed that Pin1 binds to PRDM16 and thereby promotes its degradation through the ubiquitin-proteasome system. Consistent with these results, Pin1 deletion in differentiated adipocytes showed enhancement of thermogenic programs in response to the β3 agonist CL316243 through the upregulation of PRDM16 proteins. These observations indicate that Pin1 is a negative regulator of non-shivering thermogenesis.",

author = "Yusuke Nakatsu and Yasuka Matsunaga and Takeshi Yamamotoya and Koji Ueda and Inoue, {Masa ki} and Yu Mizuno and Mikako Nakanishi and Tomomi Sano and Yosuke Yamawaki and Akifumi Kushiyama and Hideyuki Sakoda and Midori Fujishiro and Akihide Ryo and Hiraku Ono and Tohru Minamino and Takahashi, {Shin Ichiro} and Haruya Ohno and Masayasu Yoneda and Kei Takahashi and Hisamitsu Ishihara and Hideki Katagiri and Fusanori Nishimura and Takashi Kanematsu and Tetsuya Yamada and Tomoichiro Asano",

note = "Funding Information: This study was supported by a Grant-in-Aid for Scientific Research (C) ( 16K09784 to Y.N.), a Grant-in-Aid for Scientific Research on Innovative Areas (area 3702) ( 16H01392 to T.A.), and a Grant-in-Aid for Scientific Research (B) ( 17H04200 to T.A.) from the Japan Society for the Promotion of Sciences or Ministry of Education, Science, and Culture, Japan . This work was also supported by the Tsuchiya Medical Foundation , Novartis Research Grants , the Yamaguchi Endocrine Research Foundation , the Kowa Life Science Foundation , and the Institute for Adult Diseases, Asahi Life Foundation . Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = mar,

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doi = "10.1016/j.celrep.2019.02.066",

language = "English",

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T1 - Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16

AU - Nakatsu, Yusuke

AU - Matsunaga, Yasuka

AU - Yamamotoya, Takeshi

AU - Ueda, Koji

AU - Inoue, Masa ki

AU - Mizuno, Yu

AU - Nakanishi, Mikako

AU - Sano, Tomomi

AU - Yamawaki, Yosuke

AU - Kushiyama, Akifumi

AU - Sakoda, Hideyuki

AU - Fujishiro, Midori

AU - Ryo, Akihide

AU - Ono, Hiraku

AU - Minamino, Tohru

AU - Takahashi, Shin Ichiro

AU - Ohno, Haruya

AU - Yoneda, Masayasu

AU - Takahashi, Kei

AU - Ishihara, Hisamitsu

AU - Katagiri, Hideki

AU - Nishimura, Fusanori

AU - Kanematsu, Takashi

AU - Yamada, Tetsuya

AU - Asano, Tomoichiro

N1 - Funding Information: This study was supported by a Grant-in-Aid for Scientific Research (C) ( 16K09784 to Y.N.), a Grant-in-Aid for Scientific Research on Innovative Areas (area 3702) ( 16H01392 to T.A.), and a Grant-in-Aid for Scientific Research (B) ( 17H04200 to T.A.) from the Japan Society for the Promotion of Sciences or Ministry of Education, Science, and Culture, Japan . This work was also supported by the Tsuchiya Medical Foundation , Novartis Research Grants , the Yamaguchi Endocrine Research Foundation , the Kowa Life Science Foundation , and the Institute for Adult Diseases, Asahi Life Foundation . Publisher Copyright: © 2019 The Authors

PY - 2019/3/19

Y1 - 2019/3/19

N2 - Non-shivering thermogenesis in adipocytes provides defense against low temperatures and obesity development, but the underlying regulatory mechanism remains to be fully clarified. Based on both markedly increased Pin1 expression in states of excess nutrition and resistance to obesity development in Pin1 null mice, we speculated that adipocyte Pin1 may play a role in thermogenic programs. Adipose-specific Pin1 knockout (adPin1 KO) mice showed enhanced transcription of thermogenic genes and tolerance to hypothermia when exposed to cold. In addition, adPin1 KO mice were resistant to high-fat diet-induced obesity and glucose intolerance. A series of experiments revealed that Pin1 binds to PRDM16 and thereby promotes its degradation through the ubiquitin-proteasome system. Consistent with these results, Pin1 deletion in differentiated adipocytes showed enhancement of thermogenic programs in response to the β3 agonist CL316243 through the upregulation of PRDM16 proteins. These observations indicate that Pin1 is a negative regulator of non-shivering thermogenesis.

AB - Non-shivering thermogenesis in adipocytes provides defense against low temperatures and obesity development, but the underlying regulatory mechanism remains to be fully clarified. Based on both markedly increased Pin1 expression in states of excess nutrition and resistance to obesity development in Pin1 null mice, we speculated that adipocyte Pin1 may play a role in thermogenic programs. Adipose-specific Pin1 knockout (adPin1 KO) mice showed enhanced transcription of thermogenic genes and tolerance to hypothermia when exposed to cold. In addition, adPin1 KO mice were resistant to high-fat diet-induced obesity and glucose intolerance. A series of experiments revealed that Pin1 binds to PRDM16 and thereby promotes its degradation through the ubiquitin-proteasome system. Consistent with these results, Pin1 deletion in differentiated adipocytes showed enhancement of thermogenic programs in response to the β3 agonist CL316243 through the upregulation of PRDM16 proteins. These observations indicate that Pin1 is a negative regulator of non-shivering thermogenesis.

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SN - 2211-1247

VL - 26

SP - 3221-3230.e3

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -

Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16

Abstract

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