Impaired insulin signaling in the B10.D2-Hc0 H2d H2-T18c/oSnJ mouse model of complement factor 5 deficiency.
Impaired insulin signaling in the B10.D2-Hc0 H2d H2-T18c/oSnJ mouse model of complement factor 5 deficiency.
复制标题
补体因子 5 缺乏的 B10.D2-Hc0 H2d H2-T18c/oSnJ 小鼠模型中胰岛素信号传导受损。
DOI：
10.1152/ajpendo.00042.2019
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Hasty,AlyssaH
中科院分区：
文献类型：
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作者：
Peterson,KristinR;Gutierrez,DarioA;Kikuchi,Takuya;Anderson-Baucum,EmilyK;Winn,NathanC;Shuey,MeganM;Bolus,WilliamR;McGuinness,OwenP;Hasty,AlyssaH
考虑到补体因子5（C5）的化学引诱潜力及其在肥胖小鼠脂肪组织（AT）中的表达增加，我们确定了先天免疫系统的这种蛋白质是否会影响胰岛素的作用。将C5对照（C5 def）和自发C5缺陷（C5 def，B10.D2-Hc 0 H2 dH 2-T18 c/oSnJ）小鼠置于低脂肪和高脂肪饮食中以研究它们的炎症和代谢表型。使用腺病毒递送来评估外源性C5对全身代谢的影响。当喂食高脂肪饮食时，C5 def小鼠的体重增加比对照组少，伴随着AT炎症、肝脏质量和肝脏甘油三酯含量的减少。尽管有这些有益的代谢作用，C5 def小鼠表现出严重的葡萄糖耐受不良和全身性胰岛素抵抗，以及肝脏和AT中胰岛素信号传导受损。C5 def小鼠还表现出胰岛素受体（INSR）基因和蛋白表达的降低，以及pro-INSR的加工不当。这些变化不是由于C5缺陷单独的，因为其他C5缺陷模型没有重现INSR加工缺陷;相反，除了C5基因的突变，全基因组测序显示B10.D2-Hc 0 H2 dH 2-T18 c/oSnJ模型中Insr基因的内含子31-bp缺失。无论基因缺陷，腺病毒递送C5在C5 contand C5 defmice中改善胰岛素敏感性，表明C5的胰岛素增敏功能。
Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5cont) and spontaneously C5-deficient (C5def, B10.D2-Hc0H2dH2-T18c/oSnJ) mice were placed on low- and high-fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5defmice gained less weight than controls while fed a high-fat diet, accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5defmice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5defmice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. These changes were not due to the C5 deficiency alone as other C5-deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in theC5gene, whole genome sequencing revealed an intronic 31-bp deletion in theInsrgene in the B10.D2-Hc0H2dH2-T18c/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5contand C5defmice, indicating an insulin-sensitizing function of C5.