Mfge8 Binding of the avß5 Integrin Promotes Insulin Resistance in Mice

Milk fat globule EGF factor 8 (Mfge8) promotes obesity by inducing fatty acid uptake through ligation of the αvβ5 integrin. Global deletion of Mfge8 in mice increases insulin sensitivity through effects on lean body mass. The primary objective of the present study was to assess whether acute disruption of the Mfge8 signaling pathway in wild type mice modulates insulin sensitivity independent of body composition. We therefore evaluated insulin sensitivity in age and sex-matched wild type mice with insulin (ITT) and glucose tolerance tests (GTT) in the presence of a blocking antibody (ALULA) targeting the β5 integrin. Intraperitoneal administration of 5mg/kg ALULA 1h prior to ITT resulted in significantly lower blood glucose levels compared to control antibody treated mice. ALULA treated mice had a significantly lower blood glucose levels in GTT. Serum insulin level measured during GTT in ALULA treated mice was lower compared to control group, suggesting enhanced sensitivity to insulin. We validated our findings in vitro using differentiated 3T3L1 adipocytes and hepG2 liver cells. Both cell types had significantly higher uptake of the glucose analog 2NBDG after insulin treatment in presence of ALULA as compared with insulin treatment with control antibody. Insulin is known to induce glucose uptake in adipocytes through a PI3K/Akt signaling pathway. β5 integrin blockade followed by insulin administration augmented insulin mediated phosphorylation of Akt and As160 in white adipose tissue (WAT) and skeletal muscle (SM) in mice indicating that the 㬥 integrin normally dampens insulin signaling. In preliminary data we have found that after insulin treatment, the β5 integrin associates with the mature insulin receptor 㬥 (IR㬥) in WAT and SM as shown in coimmunoprecipitation studies. Further mechanistic insight to this novel regulation of IR㬥 by 㬥5 integrin will direct us towards testing the therapeutic potential of blocking 㬥5 integrin producing insulin resistance in diabetes.