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Updated: Jul 20, 2025
Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
The miR-23-27-24 clusters drive lipid-associated macrophage proliferation in obese adipose tissue
Neil T Sprenkle1, Nathan C Winn2, Kaitlyn E Bunn1
1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
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 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.
Insights
MicroRNAs regulate protective lipid-associated macrophages (LAMs), crucial for metabolic health. Loss of these microRNAs impairs LAM function, worsening insulin resistance despite reduced weight gain in obesity.
Area of Science:
- Immunology
- Metabolic Diseases
- Molecular Biology
Background:
- Adipose tissue macrophages (ATMs) play a key role in tissue homeostasis and insulin resistance.
- Understanding ATM function is critical for metabolic disease research.
Purpose of the Study:
- To identify molecular regulators of ATM function, specifically focusing on microRNAs.
- To investigate the role of miR-23-27-24 clusters in regulating lipid-associated macrophages (LAMs) and metabolic health.
Main Methods:
- Generated myeloid-specific knockout mice for miR-23-27-24 clusters.
- Analyzed ATM populations, proliferation, and function in mice on a high-fat diet.
- Utilized RNA sequencing, functional screens, and biochemical assays to identify miRNA targets.
Main Results:
- Mice lacking miR-23-27-24 clusters gained less weight but showed impaired glucose and insulin tolerance.
- A subset of protective CD9+Trem2+ ATMs (LAMs) was reduced in number and proliferation.
- miR-23 was identified as a direct regulator of Eif4ebp2, impacting macrophage proliferation.
Conclusions:
- Noncoding RNAs, specifically miR-23, control the proliferation of protective LAMs.
- This regulation is essential for preventing metabolic dysfunction associated with diet-induced obesity.
