Regulation of macrophage dynamics and adipose stromal cells by laminins during adipose tissue remodelling in obesity

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Obesity can induce an insulin resistant state in adipose tissue, liver and skeletal muscle and is strongly related to type 2 diabetes. During obesity, adipose tissue expansion is an ongoing process, characterized by hyperplasia and hypertrophy of adipocytes, accumulation of macrophages and other immune cells, and aberrant extracellular matrix deposition. Such an inflammatory state disrupts homeostasis, impairs adipocyte function and leads to insulin resistance. The Chinese partner has shown that both infiltration of blood monocytes and an unusual IL-4/STAT6 driven proliferation of tissue resident macrophages result in macrophage accumulation in obese adipose tissue. Blocking monocyte infiltration reduces obesity and resistance to insulin, suggesting different roles for tissue resident and infiltrating macrophages. While others have described distinct populations of macrophages associated with adipose tissue, the Chinese partner has shown a close association between adipose tissue macrophages (ATM) and a novel CD45negCD31negICAM-1+ population of adipose stromal cells, which represent committed preadipocytes, and localise peri-vascularly. Preliminary studies show that elimination of ICAM-1+ expression in stromal cells promotes adipocyte hyperplasia in mice on a high fat diet (HFD), suggesting that it is not ATMs alone but rather their cross-talk with ICAM+ stromal cells that is critical for fat homeostasis.Each adipocyte is encased in its own basement membrane (BM), which the German partner has shown contains mainly laminin 411, produced by stromal cells of the fat anlage. Genetic elimination of laminin 411 (Lama4-/-) reduces fat development and confers resistance to HFD induced obesity and insulin resistance. Single cell RNA analysis of wild type (WT) adipose tissue has revealed high expression of laminin 411 in the CD45negCD31negICAM-1+ adipose stromal cells. Significantly higher numbers of these cells occur Lama4-/- mice compared to WT littermates and ATMs are reduced. This suggests a central role for ICAM-1+ stromal cells in obesity and implicates laminin 411 in regulating these cells either directly and/or by altering ATM number or function. However, the relationship between laminin 411, the ICAM-1+ adipose stromal cells and ATMs remains unclear.We hypothesize that interactions between ICAM-1+ adipose stromal cells and macrophages are critical to remodelling of fat tissue during obesity and that these cell populations are regulated by laminin 411. We will investigate1. The role of ICAM-1 in lineage specification of committed preadipocytes and how this is affected by laminin 411 and macrophages;2. The contribution of tissue resident versus infiltrating macrophages to obesity and whether laminins affect macrophage infiltration or their polarization/phenotype;3. The molecular nature of interactions between ICAM-1+ adipose stromal cells and macrophage populations and whether this is affected by laminins.