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-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.