Adhesion-Related Macrophages Regulate Metabolic Homeostasis Through CAV-1 Dependency

The significance of adipose tissue macrophages (ATMs) in regulating adipose tissue function is well-established. However, our investigation revealed a previously overlooked subpopulation of macrophages adhered to adipocytes, which we term adhesion-related macrophages (ARMs). We developed an approach to isolate ARMs and compared them with stromal vascular fraction (SVF) macrophages (SMs). Our findings demonstrate that ARMs constitute the predominant expanded subpopulation of ATMs during obesity, ARMs acquire adipocyte mRNA through direct adhesion to adipocytes, thereby enhancing their lipid processing capacity. Notably, ARMs can be characterized by a key functional marker, Caveolin-1. Genetic ablation of Caveolin-1 in macrophages significantly diminishes ARM abundance, disrupting their adhesion capacity and lipid content, leading to adipocyte hypertrophy, adipose tissue expansion, and impaired glucose homeostasis. Reintroducing ARMs from lean mice into epididymal white adipose tissue (eWAT) mitigates obesity-induced insulin resistance. Our study uncovers ARM as a potential therapeutic target for obesity-induced insulin resistance and opening avenues for identifying similar paradigms in other tissues and diseases.