title: Brown adipose tissue in obesity: Fractalkine-receptor dependent immune cell recruitment affects metabolic-related gene expression.
abstract: Brown adipose tissue (BAT) plays essential role in metabolic- and thermoregulation and displays morphological and functional plasticity in response to environmental and metabolic challenges. BAT is a heterogeneous tissue containing adipocytes and various immune-related cells, however, their interaction in regulation of BAT function is not fully elucidated. Fractalkine is a chemokine synthesized by adipocytes, which recruits fractalkine receptor (CX3CR1)-expressing leukocytes into the adipose tissue. Using transgenic mice, in which the fractalkine receptor, Cx3cr1 gene was replaced by Gfp, we evaluated whether deficiency in fractalkine signaling affects BAT remodeling and function in high-fat-diet - induced obesity. Homo- and heterozygote male CX3CR1-GFP mice were fed with normal or fat enriched (FatED) diet for 10weeks. Interscapular BAT was collected for molecular biological analysis. Heterozygous animals in which fractalkine signaling remains intact, gain more weight during FatED than CX3CR1 deficient gfp/gfp homozygotes. FatED in controls resulted in macrophage recruitment to the BAT with increased expression of proinflammatory mediators (Il1a, b, Tnfa and Ccl2). Local BAT inflammation was accompanied by increased expression of lipogenic enzymes and resulted in BAT "whitening". By contrast, fractalkine receptor deficiency prevented accumulation of tissue macrophages, selectively attenuated the expression of Tnfa, Il1a and Ccl2, increased BAT expression of lipolytic enzymes (Atgl, Hsl and Mgtl) and upregulated genes involved thermo-metabolism (Ucp1, Pparg Pgc1a) in response to FatED. These results highlight the importance of fractalkine-CX3CR1 interaction in recruitment of macrophages into the BAT of obese mice which might contribute to local tissue inflammation, adipose tissue remodeling and regulation of metabolic-related genes.
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary; Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Polyák
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary; János Szentágothai Doctoral School of Neurosciences, Semmelweis University Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Winkler
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary; János Szentágothai Doctoral School of Neurosciences, Semmelweis University Budapest, Hungary.
authors.forename: Dániel
authors.initials: D
authors.lastname: Kuti
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: Szilamér
authors.initials: S
authors.lastname: Ferenczi
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary. Electronic address: kovacs@koki.hu.
authors.forename: Krisztina J
authors.initials: KJ
authors.lastname: Kovács
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1 / Q000172:deficiency / Q000378:metabolism; D003080:Cold Temperature; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008066:Lipolysis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D009929:Organ Size; D019707:Receptors, Chemokine / Q000172:deficiency / Q000378:metabolism*; D022722:Thermogenesis / Q000235:genetics; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D018836:Inflammation Mediators; D019707:Receptors, Chemokine; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D049452:Green Fluorescent Proteins
keywords: BAT; Fractalkine; Inflammation; Macrophage; Obesity; Thermogenesis; Triglyceride metabolism