DPP-4 Inhibition by Linagliptin Attenuates Obesity-Related Inflammation and Insulin Resistance by Regulating M1/M2 Macrophage Polarization

被引:171
作者
Fen Zhuge [1 ]
Ni, Yinhua [1 ]
Nagashimada, Mayumi [1 ]
Nagata, Naoto [1 ]
Xu, Liang [1 ]
Mukaida, Naofumi [2 ]
Kaneko, Shuichi [3 ]
Ota, Tsuguhito [1 ,3 ]
机构
[1] Kanazawa Univ, Dept Cell Metab & Nutr, Brain Liver Interface Med Res Ctr, Kanazawa, Ishikawa, Japan
[2] Kanazawa Univ, Div Mol Bioregulat, Canc Res Inst, Kanazawa, Ishikawa, Japan
[3] Kanazawa Univ, Grad Sch Med Sci, Dept Dis Control & Homeostasis, Kanazawa, Ishikawa, Japan
关键词
DIPEPTIDYL PEPTIDASE-4 INHIBITORS; ADIPOSE-TISSUE INFLAMMATION; LIVER-DISEASE; METABOLIC SYNDROME; SATURABLE BINDING; MONOCYTE SUBSETS; BI; 1356; MICE; CELLS; RECRUITMENT;
D O I
10.2337/db16-0317
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Dipeptidyl peptidase 4 (DPP-4) cleaves a large number of chemokine and peptide hormones involved in the regulation of the immune system. Additionally, DPP-4 may also be involved in macrophage-mediated inflammation and insulin resistance. Thus, the current study investigated the effect of linagliptin, an inhibitor of DPP-4, on macrophage migration and polarization in white adipose tissue (WAT) and liver of high-fat diet-induced obese (DIO) mice. DPP-4(+) macrophages in lean and obese mice were quantified by fluorescence-activated cell sorting (FACS) analysis. DPP-4 was predominantly expressed in F4/80(+) macrophages in crown-like structures compared with adipocytes in WAT of DIO mice. FACS analysis also revealed that, compared with chow-fed mice, DIO mice exhibited a significant increase in DPP-4+ expression in cells within adipose tissue macrophages (ATMs), particularly M1 ATMs. Linagliptin showed a greater DPP-4 inhibition and antioxidative capacity than sitagliptin and reduced M1-polarized macrophage migration while inducing an M2-dominant shift of macrophages within WAT and liver, thereby attenuating obesity-induced inflammation and insulin resistance. Loss of macrophage inflammatory protein-1 alpha, a chemokine and DPP-4 substrate, in DIO mice abrogated M2 macrophage-polarizing and insulin-sensitizing effects of linagliptin. Therefore, the inhibition of DPP-4 by linagliptin reduced obesity-related insulin resistance and inflammation by regulating M1/M2 macrophage status.
引用
收藏
页码:2966 / 2979
页数:14
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