Abstract 610: Netrin-1 Promotes Macrophage Accumulation and Insulin Resistance in Obesity

Abstract

Obesity and its co-morbidities, type 2 diabetes and cardiovascular disease, continue to increase and are a major threat to global health. Studies in mice and humans have shown that expansion of adipose tissue mass is closely associated with the recruitment of cells of the myeloid and lymphoid lineage, which gives rise to a state of chronic inflammation that contributes to insulin resistance and type 2 diabetes. The factors that regulate the metabolic-dependent accrual of macrophages in adipose are not well understood. 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. In a mouse model of diet-induced obesity, we show that adipose tissue macrophages exhibit reduced migratory capacity ex vivo, which is reversed by blocking the effects of netrin-1. In vitro, expression of netrin-1 is induced in macrophages by the saturated fatty acid palmitate, and it acts by the receptor Unc5b to block macrophage migration to the chemokine CCL19, which directs the emigration of inflammatory macrophages from tissues. Using bone marrow transplantation, we show that hematopoietic deletion of Ntn1 facilitates adipose tissue macrophage emigration to the mesenteric lymph nodes, reduces inflammation, and improves insulin sensitivity and signaling in target tissues. Collectively, these findings identify netrin-1 as a macrophage retention signal that is induced in adipose tissue during obesity, which promotes chronic inflammation and insulin resistance.