ABSTRACT
Chemerin was initially described as a chemoattractant factor for leukocyte populations. More recently, the protein has also been reported to be an adipokine, regulating adipocyte differentiation in vitro via its receptor ChemR23, and to be correlated with BMI and other parameters of the metabolic syndrome in humans. The aim of this study was to investigate the role of the chemerin/ChemR23 axis in the regulation of metabolism in vivo, using a mouse knockout (KO) model for ChemR23 (Cmklr1) in a C57BL/6 genetic background. Body weight and adipose tissue mass did not differ significantly in young animals, but were significantly higher in ChemR23 KO mice aged above 12 months. Glucose tolerance was unaffected. No significant modifications in the levels of blood lipids were observed and no increase in the levels of inflammatory markers was observed in the adipose tissue of KO mice. A high-fat diet did not exacerbate the obese phenotype in ChemR23 KO mice. No obvious defect in adipocyte differentiation was detected, while a marker of lipogenic activity (GPD1 expression) was found to be elevated. In conclusion, the chemerin/ChemR23 system does not appear to play a major role in adipocyte differentiation in vivo, but it may be involved in adipose tissue homeostasis.
Subject(s)
Adipogenesis , Aging , Chemotactic Factors/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Obesity/metabolism , Overweight/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal Transduction , Adipose Tissue, White/enzymology , Adipose Tissue, White/metabolism , Adipose Tissue, White/pathology , Adiposity , Animals , Biomarkers/metabolism , Chemokines , Chemotactic Factors/genetics , Diet, High-Fat/adverse effects , Female , Glycerolphosphate Dehydrogenase/genetics , Glycerolphosphate Dehydrogenase/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Isoenzymes/metabolism , Lipogenesis , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/etiology , Obesity/pathology , Overweight/etiology , Overweight/pathology , Receptors, Chemokine , Receptors, G-Protein-Coupled/genetics , Sex Characteristics , Weight GainABSTRACT
Chemerin is the ligand of the ChemR23 receptor and a chemoattractant factor for human immature dendritic cells (DCs), macrophages, and NK cells. In this study, we characterized the mouse chemerin/ChemR23 system in terms of pharmacology, structure-function, distribution, and in vivo biological properties. Mouse chemerin is synthesized as an inactive precursor (prochemerin) requiring, as in human, the precise processing of its C terminus for generating an agonist of ChemR23. Mouse ChemR23 is highly expressed in immature plasmacytoid DCs and at lower levels in myeloid DCs, macrophages, and NK cells. Mouse prochemerin is expressed in most epithelial cells acting as barriers for pathogens but not in leukocytes. Chemerin promotes calcium mobilization and chemotaxis on DCs and macrophages and these functional responses were abrogated in ChemR23 knockout mice. In a mouse model of acute lung inflammation induced by LPS, chemerin displayed potent anti-inflammatory properties, reducing neutrophil infiltration and inflammatory cytokine release in a ChemR23-dependent manner. ChemR23 knockout mice were unresponsive to chemerin and displayed an increased neutrophil infiltrate following LPS challenge. Altogether, the mouse chemerin/ChemR23 system is structurally and functionally conserved between human and mouse, and mouse can therefore be considered as a good model for studying the anti-inflammatory role of this system in the regulation of immune responses and inflammatory diseases.
Subject(s)
Chemotactic Factors/metabolism , Dendritic Cells/immunology , Intercellular Signaling Peptides and Proteins/metabolism , Macrophages/immunology , Pneumonia/immunology , Receptors, G-Protein-Coupled/metabolism , Acute Disease , Aequorin/immunology , Aequorin/metabolism , Animals , Apoproteins/immunology , Apoproteins/metabolism , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Calcium/immunology , Calcium/metabolism , Chemokines , Chemotactic Factors/immunology , Chemotactic Factors/pharmacology , Chemotaxis/drug effects , Chemotaxis/immunology , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Disease Models, Animal , Intercellular Signaling Peptides and Proteins/immunology , Intercellular Signaling Peptides and Proteins/pharmacology , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lipopolysaccharides/pharmacology , Lung/immunology , Lung/pathology , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/drug effects , Neutrophils/immunology , Neutrophils/metabolism , Peptides/immunology , Peptides/metabolism , Pneumonia/chemically induced , Pneumonia/metabolism , Receptors, Chemokine , Receptors, G-Protein-Coupled/genetics , Recombinant Proteins/immunology , Recombinant Proteins/metabolismABSTRACT
A model of murine toxoplasmosis was used to study cellular and temporal expression of uncoupling protein-2 (Ucp2) in the brain. In situ hybridization indicated that Ucp2 was located in neurons. Nuclei structures involved in energy balance, in particular the nucleus of the solitary tract (NST), was shown to have a positive association between negative energy balance and Ucp2 levels. Infection-induced Ucp2 expression colocalized mainly with microglial cells, but also with infiltrating macrophages and neutrophils in the brain, which was evident from day 9 post-infection. Using cytokine knockout mice we demonstrate that microglial Ucp2 induction in the brain was largely dependant on interferon-gamma, but not interleukin-6 or tumour-necrosis-factor-alpha in response to infection. In summary, this study shows that Ucp2 is regulated in a different manner in neurons than in microglia/phagocytes following infection. Our study indicates that an association exists between negative energy balance and neuronal Ucp2 levels in the NST, in particular.
