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-33(f/f) dopamine-beta -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.

Automated summary

Adaptive thermogenesis is regulated by central neuronal circuits. 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.