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

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-33^f/f dopamine-?-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.

SUBMITTER: Horie T

PROVIDER: S-EPMC7886914 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Horie Takahiro T Nakao Tetsushi T Miyasaka Yui Y Nishino Tomohiro T Matsumura Shigenobu S Nakazeki Fumiko F Ide Yuya Y Kimura Masahiro M Tsuji Shuhei S Rodriguez Randolph Ruiz RR Watanabe Toshimitsu T Yamasaki Tomohiro T Xu Sijia S Otani Chiharu C Miyagawa Sawa S Matsushita Kazuki K Sowa Naoya N Omori Aoi A Tanaka Jin J Nishimura Chika C Nishiga Masataka M Kuwabara Yasuhide Y Baba Osamu O Watanabe Shin S Nishi Hitoo H Nakashima Yasuhiro Y Picciotto Marina R MR Inoue Haruhisa H Watanabe Dai D Nakamura Kazuhiro K Sasaki Tsutomu T Kimura Takeshi T Ono Koh K

Nature communications 20210216 1

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<sup>-/-</sup> 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<sup>f/f</sup> dopamine-β-hyd ...[more]

PMID: 33594062

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Project description:Obesity is the principal symptom of metabolic syndrome, which refers to a group of risk factors that increase the likelihood of atherosclerosis. In recent decades there has been a sharp rise in the incidence of obesity throughout the developed world. Iso-α-acids, the bitter compounds derived from hops in beer, have been shown to prevent diet-induced obesity by increasing lipid oxidation in the liver and inhibition of lipid absorption from the intestine. Whereas the sharp bitterness induced by effective dose of iso-α-acids precludes their acceptance as a nutrient, matured hop bittering components (MHB) appear to be more agreeable. Therefore, we tested MHB for an effect on ameliorating diet-induced body fat accumulation in rodents. MHB ingestion had a beneficial effect but, compared to iso-α-acids and despite containing structurally similar compounds, acted via different mechanisms to reduce body fat accumulation. MHB supplementation significantly reduced body weight gain, epididymal white adipose tissue weight, and plasma non-esterified free fatty acid levels in diet-induced obese mice. We also found that uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) was significantly increased in MHB-fed mice at both the mRNA and protein levels. In addition, MHB administration in rats induced the β-adrenergic signaling cascade, which is related to cAMP accumulation in BAT, suggesting that MHB could modulate sympathetic nerve activity innervating BAT (BAT-SNA). Indeed, single oral administration of MHB elevated BAT-SNA in rats, and this elevation was dissipated by subdiaphragmatic vagotomy. Single oral administration of MHB maintained BAT temperature at a significantly higher level than in control rats. Taken together, these findings indicate that MHB ameliorates diet-induced body fat accumulation, at least partly, by enhancing thermogenesis in BAT via BAT-SNA activation. Our data suggests that MHB is a useful tool for developing functional foods or beverages to counteract the accumulation of body fat.

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

Publications

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

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