Central CCL2 signaling onto MCH neurons mediates metabolic and behavioral adaptation to inflammation. (12th October 2016)

• Record Type: Journal Article
• Authors: Le Thuc, Ophélia; Cansell, Céline; Bourourou, Miled; Denis, Raphaël GP; Stobbe, Katharina; Devaux, Nadège; Guyon, Alice; Cazareth, Julie; Heurteaux, Catherine; Rostène, William; Luquet, Serge; Blondeau, Nicolas; Nahon, Jean‐Louis; Rovère, Carole
• Is Part Of: EMBO reports. Volume 17:Number 12(2016:Dec.)
• Page Start: 1738
• Page End: 1752
• Publication Date: 2016-10-12
• Subjects: CCL2 chemokine -- CCR2 signaling pathway -- melanin‐concentrating hormone -- neuroinflammation -- weight loss; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201541499
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: CCL2/CCR2 signaling is a central relay for the behavioral and metabolic changes associated with sickness behavior in response to inflammation. Enhanced CCL2/CCR2 signaling inhibits the activity of MCH neurons in the hypothalamus and induces a decrease in body weight and food intake. LPS treatment enhances CCL2/CCR2 signaling, which can lead to inhibition of MCH neurons. LPS‐induced weight loss is mediated through CCL2/CCR2 signaling. CCR2 signaling on MCH neurons relays inflammatory signals from the periphery to the CNS to mediate sickness behavior. Abstract : CCL2/CCR2 signaling is a central relay for the behavioral and metabolic changes associated with sickness behavior in response to inflammation. Enhanced CCL2/CCR2 signaling inhibits the activity of MCH neurons in the hypothalamus and induces a decrease in body weight and food intake.