Netrin-1 promotes adipose tissue macrophage accumulation and insulin resistance in obesity

During obesity, macrophage accumulation in adipose tissue propagates the chronic inflammation and insulin resistance associated with type 2 diabetes. The factors that regulate the accrual of macrophages in adipose are not well understood. Here we show that the neuroimmune guidance cue netrin-1 is highly expressed in obese, but not lean adipose tissue of humans and mice, where it directs the retention of macrophages. Expression of netrin-1 is induced in macrophages by the saturated fatty acid palmitate, and acts via its receptor Unc5b to block macrophage migration. In a mouse model of diet-induced obesity, we show that adipose tissue macrophages exhibit reduced migratory capacity, which can be restored by blocking netrin-1. Furthermore, hematopoietic deletion of Ntn1 facilitates adipose tissue macrophage emigration, reduces inflammation, and improves insulin sensitivity. Collectively, these findings identify netrin-1 as a macrophage retention signal in adipose tissue during obesity, which promotes chronic inflammation and insulin resistance.