C-C motif chemokine receptor 9 regulates obesity-induced insulin resistance via inflammation of the small intestine in mice
C-C motif chemokine receptor 9 regulates obesity-induced insulin resistance via inflammation of the small intestine in mice
复制标题
C - C基序趋化因子受体9通过小鼠小肠炎症调节肥胖诱导的胰岛素抵抗
DOI：
10.1007/s00125-020-05349-4
复制
发表时间：
2021-01-05
期刊：
影响因子：
8.2
通讯作者：
Kanai, Takanori
中科院分区：
文献类型：
--
作者：
Amiya, Takeru;Nakamoto, Nobuhiro;Kanai, Takanori
目的/假设脂肪组织巨噬细胞的积累被认为是肥胖相关炎症和胰岛素抵抗发展的关键。此外，最近的研究表明，肠作为主要器官参与诱导高血糖症和胰岛素抵抗。我们已经报道了C-C基序趋化因子受体（CCR）CCR 9与肠道免疫相关，并且在多种肝脏疾病中具有致病作用。然而，它对2型糖尿病的贡献尚不清楚。在本研究中，我们的目的是阐明CCR 9参与2型糖尿病的病理学和潜在的潜在机制。方法为了阐明CCR 9如何影响代谢表型的发展，我们使用雄性C57 BL/6 J（野生型[WT]）和CCR 9缺陷（CCR 9敲除[KO]）小鼠喂养60%高脂饮食（HFD）12周，研究CCR 9缺陷对2型糖尿病发病机制的影响。结果WT和Ccr 9 KO小鼠喂食HFD后体重增加相当;然而，Ccr 9 KO小鼠的葡萄糖耐量和胰岛素抵抗显著改善。此外，内脏脂肪组织（VAT）和Ccr 9 KO小鼠的肝脏呈现出比WT小鼠更少的炎症和葡萄糖代谢相关基因的表达增加。Ccr 9和Ccl 25的表达在小肠中特别高，但不受HFD喂养和2型糖尿病发展的影响。在喂食HFD的WT小鼠中观察到产生IFN-γ的CD 4（+）T淋巴细胞的蓄积和小肠通透性增加，但这些变化在喂食HFD的Ccr 9 KO小鼠中受到抑制。肠嗜性CCR 9表达T淋巴细胞的连续转移通过加剧小肠和VAT中的炎症部分逆转了Ccr 9 KO小鼠中发现的有利的葡萄糖耐量。结论/解释CCR 9通过诱导小肠炎症转移在2型糖尿病的发病机制中起核心作用。我们的研究结果支持CCR 9通过肠道-VAT-肝脏轴作为2型糖尿病的新治疗靶点。
Aims/hypothesis Accumulation of adipose tissue macrophages is considered pivotal in the development of obesity-associated inflammation and insulin resistance. In addition, recent studies suggest an involvement of the intestine as the primary organ in inducing hyperglycaemia and insulin resistance. We have reported that the C-C motif chemokine receptor (CCR) CCR9 is associated with intestinal immunity and has a pathogenic role in various liver diseases. However, its contribution to type 2 diabetes is unknown. In the current study, we aimed to clarify the involvement of CCR9 in the pathology of type 2 diabetes and the potential underlying mechanisms. Methods To elucidate how CCR9 affects the development of metabolic phenotypes, we examined the impact of CCR9 deficiency on the pathogenesis of type 2 diabetes using male C57BL/6J (wild-type [WT]) and CCR9-deficient (CCR9 knockout [KO]) mice fed a 60% high-fat diet (HFD) for 12 weeks. Results WT and Ccr9KO mice fed an HFD exhibited a comparable weight gain; however, glucose tolerance and insulin resistance were significantly improved in Ccr9KO mice. Moreover, visceral adipose tissue (VAT) and the liver of Ccr9KO mice presented with less inflammation and increased expression of glucose metabolism-related genes than WT mice. Ccr9 and Ccl25 expression were specifically higher in the small intestine but was not altered by HFD feeding and type 2 diabetes development. Accumulation of IFN-gamma-producing CD4(+) T lymphocytes and increased intestinal permeability in the small intestine was observed in WT mice following HFD feeding, but these changes were suppressed in HFD-fed Ccr9KO mice. Adoptive transfer of gut-tropic CCR9-expressing T lymphocytes partially reversed the favourable glucose tolerance found in Ccr9KO mice via exacerbated inflammation in the small intestine and VAT. Conclusions/interpretation CCR9 plays a central role in the pathogenesis of type 2 diabetes by inducing an inflammatory shift in the small intestine. Our findings support CCR9 as a new therapeutic target for type 2 diabetes via the gut-VAT-liver axis.