microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity

• Published in: Nature communications Vol. 12; no. 1; pp. 843 - 17
• Main Authors: Horie, Takahiro, Nakao, Tetsushi, Miyasaka, Yui, Nishino, Tomohiro, Matsumura, Shigenobu, Nakazeki, Fumiko, Ide, Yuya, Kimura, Masahiro, Tsuji, Shuhei, Rodriguez, Randolph Ruiz, Watanabe, Toshimitsu, Yamasaki, Tomohiro, Xu, Sijia, Otani, Chiharu, Miyagawa, Sawa, Matsushita, Kazuki, Sowa, Naoya, Omori, Aoi, Tanaka, Jin, Nishimura, Chika, Nishiga, Masataka, Kuwabara, Yasuhide, Baba, Osamu, Watanabe, Shin, Nishi, Hitoo, Nakashima, Yasuhiro, Picciotto, Marina R., Inoue, Haruhisa, Watanabe, Dai, Nakamura, Kazuhiro, Sasaki, Tsutomu, Kimura, Takeshi, Ono, Koh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.02.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45/41; 64/60; 692/308/1426; 692/699/317; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - physiology; Animals; Body temperature; Body Temperature - physiology; Body Weight; Brain; Brain - metabolism; Cell Line; Circuits; Cold; Cold Temperature; Diet, High-Fat; Dopamine; Dopamine β-monooxygenase; Endoplasmic Reticulum Stress; Energy balance; Gene dosage; Genes; Humanities and Social Sciences; Humans; Hydroxylase; Hypothalamus; Integrases - metabolism; Maintenance; Male; Mice; Mice, Obese; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; multidisciplinary; Neurotransmission; Oxygen Consumption - physiology; Phenotype; Protein Subunits - genetics; Protein Subunits - metabolism; Receptors; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sympathetic nerves; Sympathetic Nervous System - physiology; Thermogenesis; Thermogenesis - genetics; γ-Aminobutyric acid; γ-Aminobutyric acid A receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21107-5

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-33 f/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-33 f/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. Adaptive thermogenesis is regulated by central neuronal circuits. Here, the authors show that microRNA-33 in the brain contributes to the maintenance of brown adipose tissue thermogenesis and whole-body energy balance via enhanced sympathetic nerve tone, and regulating the expression of GABAa receptor subunits.