title: Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity.
abstract: 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.
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Hennessy
authors.affiliation: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Ménager
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Tathagat Dutta
authors.initials: TD
authors.lastname: Ray
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Sheedy
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Hutchison
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Amarylis
authors.initials: A
authors.lastname: Wanschel
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Oldebeken
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Michele
authors.initials: M
authors.lastname: Geoffrion
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Westley
authors.initials: W
authors.lastname: Spiro
authors.affiliation: Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: George
authors.initials: G
authors.lastname: Miller
authors.affiliation: Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: Department of Surgery, New York University School of Medicine, New York, New York, USA.
authors.forename: Katey J
authors.initials: KJ
authors.lastname: Rayner
authors.affiliation: Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050152:Intra-Abdominal Fat / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D009765:Obesity / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C532445:UNC5B protein, human; D000075388:Netrin-1