title: Central CCL2 signaling onto MCH neurons mediates metabolic and behavioral adaptation to inflammation.
abstract: Sickness behavior defines the endocrine, autonomic, behavioral, and metabolic responses associated with infection. While inflammatory responses were suggested to be instrumental in the loss of appetite and body weight, the molecular underpinning remains unknown. Here, we show that systemic or central lipopolysaccharide (LPS) injection results in specific hypothalamic changes characterized by a precocious increase in the chemokine ligand 2 (CCL2) followed by an increase in pro-inflammatory cytokines and a decrease in the orexigenic neuropeptide melanin-concentrating hormone (MCH). We therefore hypothesized that CCL2 could be the central relay for the loss in body weight induced by the inflammatory signal LPS. We find that central delivery of CCL2 promotes neuroinflammation and the decrease in MCH and body weight. MCH neurons express CCL2 receptor and respond to CCL2 by decreasing both electrical activity and MCH release. Pharmacological or genetic inhibition of CCL2 signaling opposes the response to LPS at both molecular and physiologic levels. We conclude that CCL2 signaling onto MCH neurons represents a core mechanism that relays peripheral inflammation to sickness behavior.
authors.affiliation: Université Côte d'Azur, Nice, France.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Ophélia
authors.initials: O
authors.lastname: Le Thuc
authors.affiliation: Université Côte d'Azur, Nice, France.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Cansell
authors.affiliation: Université Côte d'Azur, Nice, France.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Miled
authors.initials: M
authors.lastname: Bourourou
authors.affiliation: Univ Paris Diderot Sorbonne Paris Cité Unité de Biologie Fonctionnelle et Adaptative CNRS UMR 8251, Paris, France.
authors.forename: Raphaël Gp
authors.initials: RG
authors.lastname: Denis
authors.affiliation: Université Côte d'Azur, Nice, France.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Katharina
authors.initials: K
authors.lastname: Stobbe
authors.affiliation: Université Côte d'Azur, Nice, France.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Devaux
authors.affiliation: Université Côte d'Azur, Nice, France.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Guyon
authors.affiliation: Université Côte d'Azur, Nice, France.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Cazareth
authors.affiliation: Université Côte d'Azur, Nice, France.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Heurteaux
authors.affiliation: Institut de la Vision UMRS 968-Université Pierre et Marie Curie, Paris, France.
authors.forename: William
authors.initials: W
authors.lastname: Rostène
authors.affiliation: Univ Paris Diderot Sorbonne Paris Cité Unité de Biologie Fonctionnelle et Adaptative CNRS UMR 8251, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Luquet
authors.affiliation: Université Côte d'Azur, Nice, France.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blondeau
authors.affiliation: Université Côte d'Azur, Nice, France rovere@ipmc.cnrs.fr nahonjl@ipmc.cnrs.fr.|CNRS, IPMC, Sophia Antipolis, France.|Station de Primatologie UPS846 CNRS, Rousset-sur-Arc, France.
authors.forename: Jean-Louis
authors.identifier: 0000-0001-9572-7779
authors.initials: JL
authors.lastname: Nahon
authors.affiliation: Université Côte d'Azur, Nice, France rovere@ipmc.cnrs.fr nahonjl@ipmc.cnrs.fr.|CNRS, IPMC, Sophia Antipolis, France.
authors.forename: Carole
authors.identifier: 0000-0001-9400-7972
authors.initials: C
authors.lastname: Rovère
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007028:Hypothalamic Hormones / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D055809:Illness Behavior; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008543:Melanins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000276:immunology / Q000378:metabolism*; D010907:Pituitary Hormones / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism; D015398:Signal Transduction; D015431:Weight Loss
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D007028:Hypothalamic Hormones; D008070:Lipopolysaccharides; D008543:Melanins; D010907:Pituitary Hormones; D054390:Receptors, CCR2; C019463:melanin-concentrating hormone
keywords: CCL2 chemokine; CCR2 signaling pathway; melanin‐concentrating hormone; neuroinflammation; weight loss