microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity.

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.

Citation

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, Koh Ono. microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity. Nature communications. 2021 Feb 16;12(1):843

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PMID: 33594062

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