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Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue

Significance Obesity has reached pandemic levels, prompting the need for novel therapeutics. The immune system has been suggested to be critically linked to metabolic health, leading to the prospect of immune-directed therapies. We report that obese fat tissue contains multiple distinct populations of macrophages with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. These results provide a higher resolution of the cellular and functional heterogeneity within adipose macrophages and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related inflammatory comorbidities. 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.