CD9 regulates macrophage-mediated remodeling of adipose tissue in obesity

Dysfunctional white adipose tissue contributes to the development of obesity-related morbidities, including insulin resistance, dyslipidemia, and other metabolic disorders. Adipose tissue macrophages (ATMs) accumulate in obesity and play both beneficial and harmful roles in the maintenance of adipose tissue homeostasis and function. Despite their importance, the molecules and mechanisms that regulate these diverse functions are not well understood. Lipid-associated macrophages (LAMs), the dominant subset of obesity-associated ATMs, accumulate in crown-like structures and are characterized by a metabolically activated and proinflammatory phenotype. We previously identified CD9 as a surface marker of LAMs. However, the contribution of CD9 to the activation and function of LAMs during obesity is unknown. Using a myeloid-specific CD9 knockout model, we show that CD9 supports ATM-adipocyte adhesion and crown-like structure formation. Furthermore, CD9 promotes the expression of pro-fibrotic and extracellular matrix remodeling genes. Loss of myeloid CD9 reduces adipose tissue fibrosis, increases visceral adipose tissue accumulation, and improves global metabolic outcomes during diet-induced obesity. These results identify CD9 as a causal regulator of pathogenic LAM functions, highlighting CD9 as a potential therapeutic target for treating obesity-associated metabolic disease. Overall design: Bulk RNA-seq of CD9+ and CD9- Adipose tissue macrophages isolated from male mice fed a high fat diet for 12 weeks. Samples from CD9+ adipose tissue macrophage samples from GSE113594 were reanalyzed for this study. Bulk RNA-seq of whole epididymal white adipose tissue isolated from male Control and CD9 myeloid-specific (LysMCre+/-) knockout mice fed a high fat diet for 12 weeks. *************************************************************** The table below lists GEO accessions reused/reanalyzed for this study. ***************************************************************