CCR2 modulates inflammatory and metabolic effects of high-fat feeding.
CCR2 modulates inflammatory and metabolic effects of high-fat feeding.
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DOI：
10.1172/jci24335c1
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发表时间：
2006-01
期刊：
影响因子：
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通讯作者：
S. Weisberg;Deborah Hunter;R. Huber;Jacob Lemieux;S. Slaymaker;K. Vaddi;I. Charo;R. Leibel;
中科院分区：
文献类型：
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作者：
S. Weisberg;Deborah Hunter;R. Huber;Jacob Lemieux;S. Slaymaker;K. Vaddi;I. Charo;R. Leibel;
C-C基序趋化因子受体-2（CCR 2）调节单核细胞和巨噬细胞的募集，是巨噬细胞依赖性炎症反应和动脉粥样硬化发展所必需的。虽然脂肪组织表达和循环浓度的CCL 2（也称为MCP 1），CCR 2的高亲和力配体，在肥胖症中升高，但CCR 2在代谢紊乱中的作用，包括胰岛素抵抗，肝脂肪变性和肥胖相关的炎症，尚未研究。为了确定Ccr 2在代谢表型的发展中起什么作用，我们研究了Ccr 2基因型对肥胖及其相关表型的发展的影响。Ccr 2基因缺陷减少了高脂饮食小鼠的食物摄入量，并减弱了肥胖的发展。在与肥胖症相匹配的肥胖小鼠中，Ccr 2缺乏减少了巨噬细胞含量和脂肪组织的炎症特征，增加了脂联素表达，改善了肝脏脂肪变性，并改善了全身葡萄糖稳态和胰岛素敏感性。在已确定肥胖的小鼠中，用CCR 2的药理学拮抗剂短期治疗降低了脂肪组织中的巨噬细胞含量，改善了胰岛素敏感性，而没有显著改变体重或改善肝脂肪变性。这些数据表明，CCR 2影响肥胖和相关脂肪组织炎症和全身胰岛素抵抗的发展，并且一旦肥胖及其代谢后果建立，CCR 2在维持脂肪组织巨噬细胞和胰岛素抵抗中起作用。
The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Although adipose tissue expression and circulating concentrations of CCL2 (also known as MCP1), a high-affinity ligand for CCR2, are elevated in obesity, the role of CCR2 in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity, has not been studied. To determine what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its associated phenotypes. Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet. In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity. In mice with established obesity, short-term treatment with a pharmacological antagonist of CCR2 lowered macrophage content of adipose tissue and improved insulin sensitivity without significantly altering body mass or improving hepatic steatosis. These data suggest that CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established.