Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice.
Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice.
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DOI：
10.2337/db10-1338
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发表时间：
2011-04
期刊：
影响因子：
7.7
通讯作者：
Terauchi Y
中科院分区：
文献类型：
--
作者：
Shirakawa J;Fujii H;Ohnuma K;Sato K;Ito Y;Kaji M;Sakamoto E;Koganei M;Sasaki H;Nagashima Y;Amo K;Aoki K;Morimoto C;Takeda E;Terauchi Y
饮食组成改变糖尿病患者脂肪细胞和肝细胞的代谢状态。二肽基肽酶-4（DPP-4）抑制对脂肪组织炎症和脂肪肝的影响尚不清楚。我们研究了DPP-4抑制对内脏脂肪和肝脏的胰腺外影响。我们研究了饮食诱导的β细胞特异性葡萄糖激酶单倍不足（Gck+/−）糖尿病小鼠的代谢变化。我们用含有蔗糖和油酸（SO）或蔗糖和亚油酸（SL）的组合的饮食挑战动物。接下来，我们评估了DPP-4抑制剂去氟西格列汀对脂肪组织炎症和肝脂肪变性的影响。喂食SL的Gck+/−小鼠的附睾脂肪重量和血清瘦素水平显著高于喂食SO的小鼠，尽管没有观察到体重或脂肪细胞大小的显著差异。与SO组相比，SL组内脏脂肪组织中CD 11 c + M1巨噬细胞和CD 8 + T细胞数量增加，E-选择素、P-选择素和纤溶酶原激活物抑制剂-1（派-1）表达增加。DPP-4抑制显著防止CD 8 + T细胞和M1巨噬细胞浸润脂肪组织，并降低派-1的表达。DPP-4抑制不影响活化T细胞产生细胞因子。此外，DPP-4抑制可预防野生型和Gck+/−小鼠的脂肪肝。DPP-4抑制还降低了肝脏中固醇调节元件结合蛋白-1c、硬脂酰辅酶A去饱和酶-1和脂肪酸合成酶的表达，并增加了过氧化物酶体增殖物激活受体-α的表达。我们的研究结果表明，DPP-4抑制对饮食诱导的脂肪组织炎症和肝脂肪变性具有胰腺外保护作用。
Diet composition alters the metabolic states of adipocytes and hepatocytes in diabetes. The effects of dipeptidyl peptidase-4 (DPP-4) inhibition on adipose tissue inflammation and fatty liver have been obscure. We investigated the extrapancreatic effects of DPP-4 inhibition on visceral fat and the liver. We investigated diet-induced metabolic changes in β-cell–specific glucokinase haploinsufficient (Gck+/−) diabetic mice. We challenged animals with a diet containing a combination of sucrose and oleic acid (SO) or sucrose and linoleic acid (SL). Next, we assessed the effects of a DPP-4 inhibitor, des-fluoro-sitagliptin, on adipose tissue inflammation and hepatic steatosis. The epididymal fat weight and serum leptin level were significantly higher in Gck+/− mice fed SL than in mice fed SO, although no significant differences in body weight or adipocyte size were noted. Compared with SO, SL increased the numbers of CD11c+ M1 macrophages and CD8+ T-cells in visceral adipose tissue and the expression of E-selectin, P-selectin, and plasminogen activator inhibitor-1 (PAI-1). DPP-4 inhibition significantly prevented adipose tissue infiltration by CD8+ T-cells and M1 macrophages and decreased the expression of PAI-1. The production of cytokines by activated T-cells was not affected by DPP-4 inhibition. Furthermore, DPP-4 inhibition prevented fatty liver in both wild-type and Gck+/− mice. DPP-4 inhibition also decreased the expressions of sterol regulatory element–binding protein-1c, stearoyl-CoA desaturase-1, and fatty acid synthase, and increased the expression of peroxisome proliferator–activated receptor-α in the liver. Our findings indicated that DPP-4 inhibition has extrapancreatic protective effects against diet-induced adipose tissue inflammation and hepatic steatosis.
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