Adipocyte EGFL6 Expression from Subcutaneous Adipose Tissue Alters Glucose Homeostasis and Affects Human Obesity

Recent data suggests that the adipose tissue (AT) extracellular matrix (ECM) may be a key player in the pathogenesis of obesity-related T2D. HFD feeding to collagen VI knockout mice reduces AT fibrosis (a hallmark of abnormal ECM) and improves insulin sensitivity despite an expansion of adipocyte volume. Epidermal growth factor-like-domain, multiple 6 (EGFL6) is a secreted protein best characterized for its role in tumor endothelial cell angiogenesis. Although previous studies have shown increased EGFL6 expression in whole fat of obese and insulin resistant subjects, its precise role in metabolic disease, the subtypes of cells within AT that overexpress EGFL6, and the mechanism(s) by which AT EGFL6 could modulate insulin sensitivity are entirely unknown. We obtained SAT from twenty-five lean (BMI 22.8±0.3 kg/m²) and twenty-nine obese (BMI 50.2±1.6 kg/m²) human subjects. Adipocytes and stromal vascular fraction were isolated for gene expression and co-culture experiments. We found that both adipocyte (37.21±7.55 vs. 7.44±3.67,p=0.001) and macrophage (4.69±0.79 vs. 1.15±0.45,p=0.024) EGFL6 expression was highly upregulated in human obesity; yet, only adipocyte-derived EGFL6 related significantly to insulin sensitivity (r=+0.775,p<0.001), even independent of BMI (Beta=+0.676,p<0.001). We also noted a marked difference in adipocyte EGFL6 (13.0±4.0 vs. 45.1±17.3,p=0.043) between those subjects who were insulin sensitive (HOMA-IR<3) compared to those who were insulin resistant (HOMA-IR≥3). Mechanistically, we further show that recombinant EGFL6 can directly disrupt insulin signaling in cultured adipocytes, hepatocytes, and skeletal muscle cells. Our findings linking adipocyte EGFL6 with systemic IR may lead to novel pathways involving adipocyte-derived EGFL6 and additional therapeutic targets for human T2D.