Polyák Ágnes, Winkler Zsuzsanna, Kuti Dániel, Ferenczi Szilamér, Kovács Krisztina J
Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary; Tamás Roska Doctoral School of Sciences and Technology, Pázmány Péter Catholic University, Budapest, Hungary.
Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary; János Szentágothai Doctoral School of Neurosciences, Semmelweis University Budapest, Hungary.
Biochim Biophys Acta. 2016 Nov;1861(11):1614-1622. doi: 10.1016/j.bbalip.2016.07.002. Epub 2016 Jul 12.
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.
棕色脂肪组织（BAT）在代谢和体温调节中发挥着重要作用，并在应对环境和代谢挑战时表现出形态和功能的可塑性。BAT是一种异质性组织，包含脂肪细胞和各种免疫相关细胞，然而，它们在BAT功能调节中的相互作用尚未完全阐明。趋化因子是由脂肪细胞合成的一种趋化因子，它将表达趋化因子受体（CX3CR1）的白细胞募集到脂肪组织中。我们使用转基因小鼠（其中趋化因子受体Cx3cr1基因被Gfp取代）来评估趋化因子信号通路的缺陷是否会影响高脂饮食诱导的肥胖中BAT的重塑和功能。将纯合子和杂合子雄性CX3CR1-GFP小鼠喂食正常或富含脂肪的（FatED）饮食10周。收集肩胛间BAT进行分子生物学分析。趋化因子信号通路保持完整的杂合动物在FatED期间比CX3CR1缺陷的gfp/gfp纯合子体重增加更多。对照组的FatED导致巨噬细胞募集到BAT，促炎介质（Il1a、b、Tnfa和Ccl2）的表达增加。局部BAT炎症伴随着脂肪生成酶表达的增加，并导致BAT“变白”。相比之下，趋化因子受体缺陷阻止了组织巨噬细胞的积累，选择性地减弱了Tnfa、Il1a和Ccl2的表达，增加了BAT中脂肪分解酶（Atgl、Hsl和Mgtl）的表达，并上调了响应FatED的热代谢相关基因（Ucp1、Pparg、Pgc1a）。这些结果突出了趋化因子-CX3CR1相互作用在肥胖小鼠BAT中巨噬细胞募集中的重要性，这可能有助于局部组织炎症、脂肪组织重塑和代谢相关基因的调节。
