The miR-23-27-24 clusters drive lipid-associated macrophage proliferation in obese adipose tissue

Identifying molecular circuits that control adipose tissue macrophage (ATM) function is necessary to understand how ATMs contribute to tissue homeostasis and obesity-induced insulin resistance. In this study, we find that mice with a myeloid-specific knockout of the miR-23-27-24 clusters of microRNAs (miRNAs) gain less weight on a high-fat diet but exhibit worsened glucose and insulin tolerance. Analysis of ATMs from these mice shows selectively reduced numbers and proliferation of a recently reported subset of lipid-associated CD9+Trem2+ ATMs (lipid-associated macrophages [LAMs]). Leveraging the role of miRNAs to control networks of genes, we use RNA sequencing (RNA-seq), functional screens, and biochemical assays to identify candidate target transcripts that regulate proliferation-associated signaling. We determine that miR-23 directly targets the mRNA of Eif4ebp2, a gene that restricts protein synthesis and proliferation in macrophages. Altogether, our study demonstrates that control of proliferation of a protective subset of LAMs by noncoding RNAs contributes to protection against diet-induced obesity metabolic dysfunction. [Display omitted] •miR-23-27-24 expression in myeloid cells supports glucose metabolism in obesity•Genetic deletion of miR-23-27-24 impairs Trem2+CD9+ macrophage proliferation•miR-23-27-24 regulates a network of genes in obese adipose tissue macrophages•Suppression of Eif4ebp2 by miR-23 promotes macrophage proliferation Trem2+CD9+ lipid-associated macrophage (LAM) accrual has been reported to support white adipose tissue function in obesity. Sprenkle et al. demonstrate that myeloid-specific expression of miR-23-27-24 confers protection against obesity-induced defects in glucose metabolism and promotes LAM proliferation, in part, by suppressing the expression of Eif4ebp2, a negative regulator of translation.