Female PAPP-A knockout mice are resistant to metabolic dysfunction induced by high-fat/high-sucrose feeding at middle age.
Female PAPP-A knockout mice are resistant to metabolic dysfunction induced by high-fat/high-sucrose feeding at middle age.
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DOI：
10.1007/s11357-015-9765-1
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发表时间：
2015-06-01
期刊：
影响因子：
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通讯作者：
Bartke, Andrzej
中科院分区：
文献类型：
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作者：
Hill, Cristal M;Arum, Oge;Bartke, Andrzej
胰岛素/胰岛素样生长因子(IGF)-1通路的细胞内信号共同影响寿命和衰老。异常高水平的生物活性IGF-1会增加各种癌症的发展，并可能导致代谢疾病，如胰岛素抵抗。包括妊娠相关血浆蛋白-a （PAPPA）在内的蛋白酶裂解IGF结合蛋白（igfbp）可促进IGF-1的增强。在体外，PAPP-A受促炎细胞因子（PICs）如白细胞介素(IL)-6和肿瘤坏死因子（TNF）的调节。出生时缺乏Papp-a基因的小鼠（Papp-a基因敲除（KO）小鼠）比正常的幼崽寿命长30- 40%，并且在标准饮食中IGF-1的生物活性降低。我们的目的是阐明高脂肪，高糖饮食（HFHS）如何促进肥胖，诱导代谢功能障碍，并改变PAPP-A KO和正常小鼠的全身细胞因子表达。与喂食HFHS的正常小鼠相比，喂食10周的ppp - a KO小鼠具有更高的葡萄糖耐受性和胰岛素敏感性。与喂食相同食物的正常小鼠相比，喂食HFHS的ppp -a KO小鼠的促炎细胞因子（IL-2、IL-6和tnf - α）水平较低。然而，与喂食HFHS的正常小鼠相比，喂食HFHS的ppp - a KO小鼠的抗炎细胞因子（IL-4和脂联素）水平更高。与喂食标准低脂低糖（LFLS）饮食的正常小鼠相比，喂食HFHS饮食的正常小鼠的循环ppp - a水平升高。间接量热法显示，饲喂HFHS日粮10周时，与饲喂相同日粮的正常小鼠相比，饲喂HFHS日粮的PAPP-A KO小鼠的耗氧量（VO2）显著增加。此外，与喂食HFHS的正常(N)小鼠相比，喂食HFHS的pap - a KO小鼠的呼吸商（RQ）显著降低，这表明喂食HFHS的pap - a KO小鼠能够比正常对照组更依赖脂肪作为其主要能量来源。我们得出结论，PAPP-A KO小鼠对HFHS饮食诱导的代谢功能障碍具有抗性，这些代谢功能障碍与较高水平的抗炎细胞因子和显著的代谢灵活表型相关，而HFHS饮食对正常动物的一些影响可能是由于PAPP-A水平的增加。
Longevity and aging are influenced by common intracellular signals of the insulin/insulin-like growth factor (IGF)-1 pathway. Abnormally high levels of bioactive IGF-1 increase the development of various cancers and may contribute to metabolic diseases such as insulin resistance. Enhanced availability of IGF-1 is promoted by cleavage of IGF binding proteins (IGFBPs) by proteases, including the pregnancy-associated plasma protein-A (PAPPA). In vitro, PAPP-A is regulated by pro-inflammatory cytokines (PICs) such as interleukin (IL)-6 and tumor necrosis factor (TNF). Mice born with deficiency of the Papp-a gene (PAPP-A knockout (KO) mice) live ~30-40 % longer than their normal littermates and have decreased bioactive IGF-1 on standard diets. Our objective was to elucidate how the effects of high-fat, high-sucrose diet (HFHS) promote obesity, induce metabolic dysfunction, and alter systemic cytokine expression in PAPP-A KO and normal mice. PAPP-A KO mice fed HFHS diet for 10 weeks were more glucose tolerant and had enhanced insulin sensitivity compared to normal mice fed HFHS diet. PAPP-A KO mice fed HFHS diet had lower levels of pro-inflammatory cytokines (IL-2, IL-6, and TNF-alpha) compared to normal mice fed the same diet. However, anti-inflammatory cytokine levels (IL-4 and adiponectin) were higher in PAPP-A KO mice fed HFHS diet compared to normal mice fed HFHS. Circulating PAPP-A levels were elevated in normal mice fed an HFHS diet compared to normal mice fed a standard, low-fat, low-sucrose (LFLS) diet. Indirect calorimetry showed, at 10 weeks of feeding HFHS diet, significantly increased oxygen consumption (VO2) in PAPP-A KO mice fed HFHS diet compared to normal mice fed the same diet. Furthermore, respiratory quotient (RQ) was significantly lower in PAPP-A KO mice fed HFHS diet compared to normal (N) mice fed HFHS diet indicating PAPP-A KO mice fed HFHS diet are able to rely on fat as their primary source of energy more so than normal controls. We conclude that PAPP-A KO mice are resistant to the HFHS diet induction of metabolic dysfunction associated with higher levels of anti-inflammatory cytokines and a remarkably metabolic flexible phenotype and that some of the effects of HFHS diet in normal animals may be due to increased levels of PAPP-A.