Microglial ALKBH5 loss protects fat browning in aging male mice

In male mice, researchers examined how hypothalamic microglia regulate sympathetic innervation and adipose tissue browning. Using single-nucleus RNA sequencing, brain slice electrophysiology, and tissue pathology, the authors demonstrated that the RNA m6A demethylase ALKBH5 in microglia of the paraventricular hypothalamus inhibits cold exposure-induced adipocyte browning in subcutaneous white adipose tissue. Microglia-specific knockout of ALKBH5 increased m6A methylation of Ntf5 mRNA and upregulated microglial Ntf5 expression. This signaling activated TrkB-positive paraventricular hypothalamus neurons and downstream sympathetic innervation to subcutaneous fat. During aging, microglia-specific ALKBH5 knockout prevented the loss of brown adipocytes in subcutaneous white adipose tissue and promoted metabolic activity.