microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity

Takahiro Horie (), Tetsushi Nakao, Yui Miyasaka, Tomohiro Nishino, Shigenobu Matsumura, Fumiko Nakazeki, Yuya Ide, Masahiro Kimura, Shuhei Tsuji, Randolph Ruiz Rodriguez, Toshimitsu Watanabe, Tomohiro Yamasaki, Sijia Xu, Chiharu Otani, Sawa Miyagawa, Kazuki Matsushita, Naoya Sowa, Aoi Omori, Jin Tanaka, Chika Nishimura, Masataka Nishiga, Yasuhide Kuwabara, Osamu Baba, Shin Watanabe, Hitoo Nishi, Yasuhiro Nakashima, Marina R. Picciotto, Haruhisa Inoue, Dai Watanabe, Kazuhiro Nakamura, Tsutomu Sasaki, Takeshi Kimura and Koh Ono ()
Additional contact information
Takahiro Horie: Kyoto University
Tetsushi Nakao: Kyoto University
Yui Miyasaka: Kyoto University
Tomohiro Nishino: Kyoto University
Shigenobu Matsumura: Kyoto University
Fumiko Nakazeki: Kyoto University
Yuya Ide: Kyoto University
Masahiro Kimura: Kyoto University
Shuhei Tsuji: Kyoto University
Randolph Ruiz Rodriguez: Kyoto University
Toshimitsu Watanabe: Kyoto University
Tomohiro Yamasaki: Kyoto University
Sijia Xu: Kyoto University
Chiharu Otani: Kyoto University
Sawa Miyagawa: Kyoto University
Kazuki Matsushita: Kyoto University
Naoya Sowa: Kyoto University
Aoi Omori: Kyoto University
Jin Tanaka: Kyoto University
Chika Nishimura: Kyoto University
Masataka Nishiga: Kyoto University
Yasuhide Kuwabara: Kyoto University
Osamu Baba: Kyoto University
Shin Watanabe: Kyoto University
Hitoo Nishi: Kyoto University
Yasuhiro Nakashima: Kyoto University
Marina R. Picciotto: Yale University School of Medicine
Haruhisa Inoue: Kyoto University
Dai Watanabe: Kyoto University
Kazuhiro Nakamura: Nagoya University Graduate School of Medicine
Tsutomu Sasaki: Kyoto University
Takeshi Kimura: Kyoto University
Koh Ono: Kyoto University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Adaptive thermogenesis is essential for survival, and therefore is tightly regulated by a central neural circuit. Here, we show that microRNA (miR)-33 in the brain is indispensable for adaptive thermogenesis. Cold stress increases miR-33 levels in the hypothalamus and miR-33−/− mice are unable to maintain body temperature in cold environments due to reduced sympathetic nerve activity and impaired brown adipose tissue (BAT) thermogenesis. Analysis of miR-33f/f dopamine-β-hydroxylase (DBH)-Cre mice indicates the importance of miR-33 in Dbh-positive cells. Mechanistically, miR-33 deficiency upregulates gamma-aminobutyric acid (GABA)A receptor subunit genes such as Gabrb2 and Gabra4. Knock-down of these genes in Dbh-positive neurons rescues the impaired cold-induced thermogenesis in miR-33f/f DBH-Cre mice. Conversely, increased gene dosage of miR-33 in mice enhances thermogenesis. Thus, miR-33 in the brain contributes to maintenance of BAT thermogenesis and whole-body metabolism via enhanced sympathetic nerve tone through suppressing GABAergic inhibitory neurotransmission. This miR-33-mediated neural mechanism may serve as a physiological adaptive defense mechanism for several stresses including cold stress.

Date: 2021
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DOI: 10.1038/s41467-021-21107-5

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