The miR-23-27-24 clusters drive lipid-associated macrophage proliferation in obese adipose tissue
Neil T. Sprenkle,
Nathan C. Winn,
Kaitlyn E. Bunn,
Yang Zhao,
Deborah J. Park,
Brenna G. Giese,
John J. Karijolich,
K. Mark Ansel,
C. Henrique Serezani,
Alyssa H. Hasty,
Heather H. Pua
Affiliations
Neil T. Sprenkle
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Nathan C. Winn
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
Kaitlyn E. Bunn
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Yang Zhao
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Deborah J. Park
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Brenna G. Giese
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
John J. Karijolich
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Center for Immunobiology and Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanerbilt-Ingram Cancer Center, Nashville, TN, USA
K. Mark Ansel
Department of Microbiology and Immunology and Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, USA
C. Henrique Serezani
Vanderbilt Center for Immunobiology and Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Alyssa H. Hasty
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Vanderbilt Center for Immunobiology and Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
Heather H. Pua
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Center for Immunobiology and Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA; Corresponding author
Summary: 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.
