Fpr2 Deficiency Alleviates Diet-Induced Insulin Resistance Through Reducing Body Weight Gain and Inhibiting Inflammation Mediated by Macrophage Chemotaxis and M1 Polarization
Fpr2 Deficiency Alleviates Diet-Induced Insulin Resistance Through Reducing Body Weight Gain and Inhibiting Inflammation Mediated by Macrophage Chemotaxis and M1 Polarization
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Fpr2 缺乏可通过减少体重增加和抑制巨噬细胞趋化性和 M1 极化介导的炎症来减轻饮食引起的胰岛素抵抗
DOI：
10.2337/db18-0469
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发表时间：
2019-06-01
期刊：
影响因子：
7.7
通讯作者：
Le, Yingying
中科院分区：
文献类型：
--
作者：
Chen, Xiaofang;Zhuo, Shu;Le, Yingying
肥胖和相关的炎症在胰岛素抵抗的发病机制中起着关键作用，但其潜在的机制尚不完全清楚。甲酰肽受体2(FPR2)在宿主免疫反应和炎症相关疾病中发挥重要作用。我们发现在高脂饮食(HFD)诱导的肥胖小鼠和db/db小鼠的白色脂肪组织中，Fpr2的表达增加。Fpr2基因的系统性缺失可缓解高脂饲料引起的肥胖、胰岛素抵抗、高血糖、高脂血症和肝脏脂肪变性。此外，Fpr2基因缺失通过减少代谢组织中巨噬细胞的渗透和M1极化，提高了体温，减少了脂肪质量，并抑制了炎症。野生型和Fpr2−/−小鼠之间的骨髓移植和髓系特异性Fpr2缺失表明，表达Fpr2的髓系细胞加剧了高脂饮食诱导的肥胖、胰岛素抵抗、糖脂代谢紊乱和炎症。机制研究表明，Fpr2缺失可能通过增加骨骼肌产热增加能量消耗；血清淀粉样蛋白A3和其他由脂肪细胞分泌的因子通过Fpr2诱导巨噬细胞趋化；Fpr2缺失通过阻断信号抑制巨噬细胞趋化和脂多糖、棕榈酸酯和干扰素γ诱导的巨噬细胞M1极化。总之，我们的研究表明，髓系Fpr2通过调节肌肉能量消耗、巨噬细胞趋化和M1极化，在肥胖和相关的代谢紊乱中发挥关键作用。
Obesity and related inflammation are critical for the pathogenesis of insulin resistance, but the underlying mechanisms are not fully understood. Formyl peptide receptor 2 (FPR2) plays important roles in host immune responses and inflammation-related diseases. We found that Fpr2 expression was elevated in the white adipose tissue of high-fat diet (HFD)–induced obese mice and db/db mice. The systemic deletion of Fpr2 alleviated HFD-induced obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis. Furthermore, Fpr2 deletion in HFD-fed mice elevated body temperature, reduced fat mass, and inhibited inflammation by reducing macrophage infiltration and M1 polarization in metabolic tissues. Bone marrow transplantations between wild-type and Fpr2−/− mice and myeloid-specific Fpr2 deletion demonstrated that Fpr2-expressing myeloid cells exacerbated HFD-induced obesity, insulin resistance, glucose/lipid metabolic disturbances, and inflammation. Mechanistic studies revealed that Fpr2 deletion in HFD-fed mice enhanced energy expenditure probably through increasing thermogenesis in skeletal muscle; serum amyloid A3 and other factors secreted by adipocytes induced macrophage chemotaxis via Fpr2; and Fpr2 deletion suppressed macrophage chemotaxis and lipopolysaccharide-, palmitate-, and interferon-γ–induced macrophage M1 polarization through blocking their signals. Altogether, our studies demonstrate that myeloid Fpr2 plays critical roles in obesity and related metabolic disorders via regulating muscle energy expenditure, macrophage chemotaxis, and M1 polarization.