Critical roles of nardilysin in the maintenance of body temperature homoeostasis

Yoshinori Hiraoka, Tatsuhiko Matsuoka, Mikiko Ohno, Kazuhiro Nakamura, Sayaka Saijo, Shigenobu Matsumura, Kiyoto Nishi, Jiro Sakamoto, Po-Min Chen, Kazuo Inoue, Tohru Fushiki, Toru Kita, Takeshi Kimura and Eiichiro Nishi ()
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Yoshinori Hiraoka: Graduate School of Medicine, Kyoto University
Tatsuhiko Matsuoka: Graduate School of Medicine, Kyoto University
Mikiko Ohno: Graduate School of Medicine, Kyoto University
Kazuhiro Nakamura: Career-Path Promotion Unit for Young Life Scientists, Kyoto University
Sayaka Saijo: Graduate School of Medicine, Kyoto University
Shigenobu Matsumura: Laboratory of Nutrition Chemistry, Graduate School of Agriculture, Kyoto University
Kiyoto Nishi: Graduate School of Medicine, Kyoto University
Jiro Sakamoto: Graduate School of Medicine, Kyoto University
Po-Min Chen: Graduate School of Medicine, Kyoto University
Kazuo Inoue: Laboratory of Nutrition Chemistry, Graduate School of Agriculture, Kyoto University
Tohru Fushiki: Laboratory of Nutrition Chemistry, Graduate School of Agriculture, Kyoto University
Toru Kita: Kobe City Medical Center General Hospital
Takeshi Kimura: Graduate School of Medicine, Kyoto University
Eiichiro Nishi: Graduate School of Medicine, Kyoto University

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Body temperature homoeostasis in mammals is governed centrally through the regulation of shivering and non-shivering thermogenesis and cutaneous vasomotion. Non-shivering thermogenesis in brown adipose tissue (BAT) is mediated by sympathetic activation, followed by PGC-1α induction, which drives UCP1. Here we identify nardilysin (Nrd1 and NRDc) as a critical regulator of body temperature homoeostasis. Nrd1−/− mice show increased energy expenditure owing to enhanced BAT thermogenesis and hyperactivity. Despite these findings, Nrd1−/− mice show hypothermia and cold intolerance that are attributed to the lowered set point of body temperature, poor insulation and impaired cold-induced thermogenesis. Induction of β3-adrenergic receptor, PGC-1α and UCP1 in response to cold is severely impaired in the absence of NRDc. At the molecular level, NRDc and PGC-1α interact and co-localize at the UCP1 enhancer, where NRDc represses PGC-1α activity. These findings reveal a novel nuclear function of NRDc and provide important insights into the mechanism of thermoregulation.

Date: 2014
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DOI: 10.1038/ncomms4224

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