Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes
Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes
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DOI：
10.1007/s00125-012-2592-3
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发表时间：
2012-09-01
期刊：
影响因子：
8.2
通讯作者：
Jun, H. -S.
中科院分区：
文献类型：
--
作者：
Lee, Y. -S.;Park, M. -S.;Jun, H. -S.
肥胖和胰岛素抵抗与低度慢性炎症有关。已知胰高血糖素样肽-1（GLP-1）可降低胰岛素抵抗。我们研究了GLP-1是否对脂肪组织（包括脂肪细胞和脂肪组织巨噬细胞（ATM））具有抗炎作用。我们将产生GLP-1的重组腺病毒（rAd）（rAd-GLP-1）给予ob/ob小鼠糖尿病模型。我们检测了胰岛素敏感性、体脂量、ATM浸润和代谢特征。我们通过实时定量PCR分析了脂肪组织中炎性细胞因子、脂肪生成基因以及M1和M2巨噬细胞特异性基因的mRNA表达。我们还检测了核因子-κ B（NF-κ B B）、细胞外信号调节激酶1/2和Jun N-末端激酶（JNK）在体内和体外的活化情况。在rAd-GLP-1处理的ob/ob小鼠的脂肪组织中，巨噬细胞群（F4/80（+）和F4/80（+）CD 11b（+）CD 11 c（+）细胞）以及IL-6、TNF-α和单核细胞趋化蛋白-1的表达和产生显著降低。在rAd-GLP-1处理的ob/ob小鼠中，M1特异性mRNA的表达显著降低，但M2特异性mRNA的表达无变化。rAd-GLP-1处理的ob/ob小鼠脂肪组织中NF-κ B和JNK活化显著降低。在3 T3-L1脂肪细胞和ATM中，GLP-1受体激动剂exendin-4可减少脂多糖诱导的炎症。我们认为GLP-1可减少巨噬细胞浸润，并直接抑制脂肪细胞和ATM中的炎症通路，可能有助于改善胰岛素敏感性。
Obesity and insulin resistance are associated with low-grade chronic inflammation. Glucagon-like peptide-1 (GLP-1) is known to reduce insulin resistance. We investigated whether GLP-1 has anti-inflammatory effects on adipose tissue, including adipocytes and adipose tissue macrophages (ATM).We administered a recombinant adenovirus (rAd) producing GLP-1 (rAd-GLP-1) to an ob/ob mouse model of diabetes. We examined insulin sensitivity, body fat mass, the infiltration of ATM and metabolic profiles. We analysed the mRNA expression of inflammatory cytokines, lipogenic genes, and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR. We also examined the activation of nuclear factor kappa B (NF-kappa B), extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase (JNK) in vivo and in vitro.Fat mass, adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Macrophage populations (F4/80(+) and F4/80(+)CD11b(+)CD11c(+) cells), as well as the expression and production of IL-6, TNF-alpha and monocyte chemoattractant protein-1, were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Expression of M1-specific mRNAs was significantly reduced, but that of M2-specific mRNAs was unchanged in rAd-GLP-1-treated ob/ob mice. NF-kappa B and JNK activation was significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Lipopolysaccharide-induced inflammation was reduced by the GLP-1 receptor agonist, exendin-4, in 3T3-L1 adipocytes and ATM.We suggest that GLP-1 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and ATM, possibly contributing to the improvement of insulin sensitivity.