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

Obesity is marked by a state of low-grade inflammation, including the accumulation of macrophages in the adipose tissue, which results in insulin resistance. Kathryn Moore and her colleagues now show that the neuronal guidance molecule, netrin-1, is upregulated in fat cells during obesity and leads to the retention of macrophages in this tissue. They also show that its genetic deletion in mice prevents the development of insulin resistance by a high-fat diet. During obesity, macrophage accumulation in adipose tissue propagates the chronic inflammation and insulin resistance associated with type 2 diabetes. The factors, however, that regulate the accrual of macrophages in adipose tissue 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. Netrin-1, whose expression is induced in macrophages by the saturated fatty acid palmitate, acts via its receptor Unc5b to block their 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 that promotes chronic inflammation and insulin resistance.