The miR-23-27-24 Clusters Drive Lipid-Associated Macrophage Proliferation in Obese Adipose Tissue

Abstract

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 found that mice with a myeloid-specific knockout of the miR-23-27-24 clusters of miRNAs gained less weight on a high-fat diet but exhibited worsened glucose and insulin tolerance. Analysis of ATMs from these mice revealed selectively reduced numbers and proliferation of a recently reported subset of lipid-associated CD9+Trem2+ ATMs (LAMs). Leveraging the role of miRNAs to control networks of genes, we used RNA sequencing, functional screens, and biochemical assays to identify candidate target transcripts that regulate proliferation-associated signaling. We determined that Eif4ebp2 is a direct target of miR-23, which we found to inhibit 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.