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.

Automated summary

This study shows that knockout of the miR-23-27-24 miRNA gene cluster in mice leads to reduced weight gain on a high-fat diet but worsened glucose and insulin tolerance. Further analysis reveals decreased numbers and proliferation of a subset of lipid-associated CD9+Trem2+ ATMs in the adipose tissue of these mice. The researchers identify Eif4ebp2 mRNA as a direct target of miR-23, a gene that regulates protein synthesis and proliferation in macrophages. Overall, this study highlights the importance of noncoding RNAs in controlling the proliferation of protective macrophages in adipose tissue, thus impacting metabolic dysfunction associated with diet-induced obesity.