title: Neuropeptide Y1 receptor in immune cells regulates inflammation and insulin resistance associated with diet-induced obesity.
abstract: Recruitment of activated immune cells into white adipose tissue (WAT) is linked to the development of insulin resistance and obesity, but the mechanism behind this is unclear. Here, we demonstrate that Y1 receptor signaling in immune cells controls inflammation and insulin resistance in obesity. Selective deletion of Y1 receptors in the hematopoietic compartment of mice leads to insulin resistance and inflammation in WAT under high fat-fed conditions. This is accompanied by decreased mRNA expression of the anti-inflammatory marker adiponectin in WAT and an increase of the proinflammatory monocyte chemoattractant protein-1 (MCP-1). In vitro, activated Y1-deficient intraperitoneal macrophages display an increased inflammatory response, with exacerbated secretion of MCP-1 and tumor necrosis factor, whereas addition of neuropeptide Y to wild-type macrophages attenuates the release of these cytokines, this effect being blocked by Y1 but not Y2 receptor antagonism. Importantly, treatment of adipocytes with the supernatant of activated Y1-deficient macrophages causes insulin resistance, as demonstrated by decreased insulin-induced phosphorylation of the insulin receptor and Akt as well as decreased expression of insulin receptor substrate 1. Thus, Y1 signaling in hematopoietic-derived cells such as macrophages is critical for the control of inflammation and insulin resistance in obesity.
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Laurence
authors.initials: L
authors.lastname: Macia
authors.forename: Ernie
authors.initials: E
authors.lastname: Yulyaningsih
authors.forename: Laurent
authors.initials: L
authors.lastname: Pangon
authors.forename: Amy D
authors.initials: AD
authors.lastname: Nguyen
authors.forename: Shu
authors.initials: S
authors.lastname: Lin
authors.forename: Yan C
authors.initials: YC
authors.lastname: Shi
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Martijn
authors.initials: M
authors.lastname: Bijker
authors.forename: Shane
authors.initials: S
authors.lastname: Grey
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.forename: Amanda
authors.initials: A
authors.lastname: Sainsbury
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002454:Cell Differentiation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects; D004435:Eating / Q000235:genetics / Q000502:physiology; D005260:Female; D005838:Genotype; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000276:immunology* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D004041:Dietary Fats; D017476:Receptors, Neuropeptide Y; D014409:Tumor Necrosis Factor-alpha; C097212:neuropeptide Y-Y1 receptor