Role of Macrophage PARP1 in the Regulation of Crosstalk between Adipose Immune Cells and Adipocytes during Diet-induced Obesity

Adipose tissue consists of heterogeneous cell populations, including macrophages, which play a key role in maintaining adipose tissue homeostasis. We previously identified PARP1 as a critical regulator of proadipogenic gene expression in preadipocytes and proinflammatory gene expression in macrophages. To investigate the role of macrophage PARP1 in regulating adipose tissue homeostasis, we generated myeloid lineage-specific Parp1 knockout mice ( Parp1 KO ^LysM ). When subjected to a high fat diet for 12 weeks, the Parp1 KO ^LysM mice exhibited an obese phenotype accompanied by white adipose tissue (WAT) dysfunction, characterized by altered metabolite profile, pronounced adipocyte hypertrophy, and increased macrophage infiltration. Coculture of primary preadipocytes with the conditioned medium from bone marrow-derived macrophages (BMDMs) isolated from Parp1 KO ^LysM or control mice demonstrated that macrophage PARP1 depletion inhibited LPS-induced proinflammatory gene expression in BMDMs, but enhanced differentiation of preadipocytes into mature adipocytes. Single cell RNA-sequencing using CD45 ⁺ -sorted WAT resident immune cells showed that macrophage PARP1 depletion increased the fraction of macrophages and NK cells, altered gene expression in both cell populations, and promoted intercellular communications. Taken together, our studies demonstrate a key role for macrophage PARP1 in the maintenance of adipose tissue inflammatory and metabolic homeostasis. Macrophage PARP1 depletion promotes cell-cell crosstalk among macrophages, fat cells, and other immune cell populations in adipose tissue, which cooperatively drives the development of obesity.