CCR9或调控肥胖诱导的胰岛素抵抗
创作:吴芹 审核:爱的抉择 01月28日
  • 高脂饮食(HFD)导致野生型和CCR9 敲除小鼠体重增加类似,但CCR9 KO缓解葡萄糖耐受和胰岛素抵抗,内脏脂肪组织(VAT)和肝脏炎症较少,葡萄糖代谢相关基因表达较高;
  • 小肠中,Ccr9和Ccl25表达较高,HFD和2型糖尿病不改变其表达;
  • HFD导致小肠内IFN-γ+ CD4+ T细胞的积累和肠道通透性增加,导致炎症,而CCR9 KO抑制这些变化;
  • 移植表达CCR9的T细胞到CCR9 KO小鼠肠道,可加剧小肠和VAT的炎症,部分逆转CCR9 KO对葡萄糖耐受的有益作用。
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爱的抉择
CCR9与肠道免疫有关,在多种肝脏疾病中有致病作用。肠道可作为诱发高血糖和胰岛素抵抗的主要器官,而CCR9对2型糖尿病的影响尚不清楚。Diabetologia近期发表的文章,发现CCR9通过诱导小肠炎症,在2型糖尿病的病理发生中具有重要作用,提示CCR9可能成为通过肠-VAT-肝轴治疗2型糖尿病的新靶点。
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Diabetologia [IF:7.518]

C-C motif chemokine receptor 9 regulates obesity-induced insulin resistance via inflammation of the small intestine in mice

CCR9通过小鼠小肠炎症调节肥胖诱导的胰岛素抵抗

10.1007/s00125-020-05349-4

01-05, Article

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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-γ-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.

First Authors:
Takeru Amiya

Correspondence Authors:
Nobuhiro Nakamoto,Takanori Kanai

All Authors:
Takeru Amiya,Nobuhiro Nakamoto,Junichiro Irie,Nobuhito Taniki,Po-Sung Chu,Yuzo Koda,Kentaro Miyamoto,Akihiro Yamaguchi,Shunsuke Shiba,Rei Morikawa,Hiroshi Itoh,Takanori Kanai

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