Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 22, Pages E5096-E5105Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1802611115
Keywords
macrophage; adipose tissue; exosome; obesity; inflammation
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Funding
- NIH [DK49780, T32 HD043021, F30 DK112507, K08 NHLBI 132099]
- Penn Mental Health AIDS Research Center [P30 MH097488]
- JPB Foundation
- Children's Hospital of Philadelphia Senior Fellow K-readiness grant
- American Heart Association Postdoctoral Fellowship [16POST29680002]
- Functional Genomics Core and Human Metabolic Tissue Bank of the Penn Diabetes Research Center [P30 DK19525]
- Penn Flow-Cytometry and Cell Sorting Core, Histology and Gene Expression Core
- Cell and Developmental Biology Microscopy Core
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Obesity is characterized by an accumulation of macrophages in adipose, some of which form distinct crown-like structures (CLS) around fat cells. While multiple discrete adipose tissue macrophage (ATM) subsets are thought to exist, their respective effects on adipose tissue, and the transcriptional mechanisms that underlie the functional differences between ATM subsets, are not well understood. We report that obese fat tissue of mice and humans contain multiple distinct populations of ATMs with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. Mouse Ly6c ATMs reside outside of CLS and are adipogenic, while CD9 ATMs reside within CLS, are lipid-laden, and are proinflammatory. Adoptive transfer of Ly6c ATMs into lean mice activates gene programs typical of normal adipocyte physiology. By contrast, adoptive transfer of CD9 ATMs drives gene expression that is characteristic of obesity. Importantly, human adipose tissue contains similar ATM populations, including lipid-laden CD9 ATMs that increase with body mass. These results provide a higher resolution of the cellular and functional heterogeneity within ATMs and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related sequela.
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