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

Cell Rep. 2019 Mar 19;26(12):3221-3230.e3. doi: 10.1016/j.celrep.2019.02.066.

Authors

Yusuke Nakatsu¹, Yasuka Matsunaga¹, Takeshi Yamamotoya¹, Koji Ueda¹, Masa-Ki Inoue¹, Yu Mizuno¹, Mikako Nakanishi¹, Tomomi Sano², Yosuke Yamawaki³, Akifumi Kushiyama⁴, Hideyuki Sakoda⁵, Midori Fujishiro⁶, Akihide Ryo⁷, Hiraku Ono⁸, Tohru Minamino⁹, Shin-Ichiro Takahashi¹⁰, Haruya Ohno¹¹, Masayasu Yoneda¹¹, Kei Takahashi¹², Hisamitsu Ishihara⁶, Hideki Katagiri¹², Fusanori Nishimura², Takashi Kanematsu³, Tetsuya Yamada¹³, Tomoichiro Asano¹⁴

Affiliations

¹ Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima City, Hiroshima 734-8553, Japan.
² Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka City, Fukuoka 812-8582, Japan.
³ Department of Cellular and Molecular Pharmacology, Division of Basic Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima City, Hiroshima 734-8553, Japan.
⁴ The Division of Diabetes and Metabolism, Institute for Adult Diseases, Asahi Life Foundation, Chuo-ku, Tokyo 103-0002, Japan.
⁵ Department of Internal Medicine, The Division of Neurology, Respirology, Endocrinology, and Metabolism, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
⁶ The Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan.
⁷ The Department of Microbiology, Yokohama City University of Medicine, Yokohama City, Kanagawa 263-0004, Japan.
⁸ Department of Clinical Cell Biology, Chiba University Graduate School of Medicine, Chiba City, Chiba 260-8677, Japan.
⁹ Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata 951-8510, Japan.
¹⁰ Department of Animal Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8567, Japan; Department of Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8567, Japan.
¹¹ Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima City, Hiroshima 734-8553, Japan.
¹² Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
¹³ Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
¹⁴ Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima City, Hiroshima 734-8553, Japan. Electronic address: tasano@hiroshima-u.ac.jp.

PMID: 30893596
DOI: 10.1016/j.celrep.2019.02.066

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.

Keywords: PRDM16; Pin1; UCP-1; obesity; thermogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / cytology
Adipocytes / metabolism*
Animals
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Mice
Mice, Knockout
NIMA-Interacting Peptidylprolyl Isomerase / genetics
NIMA-Interacting Peptidylprolyl Isomerase / metabolism*
Protein Binding
Proteolysis*
Thermogenesis / physiology*
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic / physiology
Ubiquitination / physiology

Substances

DNA-Binding Proteins
NIMA-Interacting Peptidylprolyl Isomerase
Prdm16 protein, mouse
Transcription Factors
Pin1 protein, mouse