1494-P: Gr1⁺ Myeloid Cell Governs Adipose Tissue Remodeling via Controlling Macrophage Infiltration

Introduction & Objective: Pathological adipose tissue remodeling contributed to the development of insulin resistance and type 2 diabetes. The aberrant myeloid phenotype has recently been implicated in driving the diabetic environment. However, the role of myeloid cells in adipose remodeling remains largely unknown.

Methods: C57BL6/J mice were i.p. injected with either Gr-1 or IgG2b isotype control antibody once a week for 2 dose to temporarily eliminate Gr-1⁺ myeloid cells. Metabolic status was assessed by GTT and ITT. Adipose tissues were harvested for histological, immunostaining, and RNA-seq analysis.

Results: In lean mice, elimination of Gr-1⁺ cells led to a reduction in gWAT weight. Histologic analysis showed smaller adipocytes, augmented collagen deposition and evaluated expression of a major ECM receptor CD44 in gWAT upon Gr-1 depletion. Ablation of Gr-1⁺ cells resulted in increased serum level of MCP-1 and more iNOS⁺CD206⁻ M1 macrophages in gWAT. Interestingly, in spite of no difference was observed in ITT, Gr-1 ablation increased glucose clearance in mice, which was associated with enhanced glycogen deposition in liver and muscle. The KEGG enrichment analysis of RNA-seq data from gWAT revealed that genes with increased expression upon Gr-1 depletion were mainly clustered in regulation of lipolysis in adipocytes, leukocyte transendothelial migration, and ECM-receptor interaction. Besides, GSEA showed a significant enrichment of gene sets associated with TNF signaling pathway, type I diabetes mellitus and insulin resistance.

Conclusion: Acute depletion of Gr-1⁺ cells promoted the macrophage infiltration and polarization towards a M1 phenotype in gWAT. This pro-inflammatory milieu would contribute to metabolic dysfunction, such as adipose tissue remodeling, aggravated lipolysis and insulin resistance. Our data suggested that Gr-1⁺ myeloid cell might be a key regulator against pathological adipose tissue remodeling by restricting macrophage infiltration.