Loss of angiopoietin-like 4 (ANGPTL4) in mice with diet-induced obesity uncouples visceral obesity from glucose intolerance partly via the gut microbiota.
Loss of angiopoietin-like 4 (ANGPTL4) in mice with diet-induced obesity uncouples visceral obesity from glucose intolerance partly via the gut microbiota.
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DOI：
10.1007/s00125-018-4583-5
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发表时间：
2018-06
期刊：
影响因子：
8.2
通讯作者：
Kersten S
中科院分区：
文献类型：
--
作者：
Janssen AWF;Katiraei S;Bartosinska B;Eberhard D;Willems van Dijk K;Kersten S
血管生成素样4 （ANGPTL4）是三酰基甘油代谢的重要调节因子，通过抑制脂蛋白脂肪酶和胰脂肪酶来实现这一作用。ANGPTL4是改善心脏代谢疾病的潜在靶点。虽然ANGPTL4与肥胖有关，但ANGPTL4在饮食诱导的肥胖和相关代谢功能障碍中的直接作用的研究受到大量急性期反应和喂养标准高脂肪饮食的ANGPTL4 - / -小鼠致死性乳糜腹水和腹膜炎的发展的阻碍。本研究的目的是更好地表征ANGPTL4在肥胖期间葡萄糖稳态和代谢功能障碍中的作用。我们长期给野生型（WT）和Angptl4 - / -小鼠喂食富含不饱和脂肪酸和胆固醇的饮食，并在饮用水中添加果糖，研究其代谢功能。通过口服抗生素（氨苄西林、新霉素、甲硝唑）的混合物来研究肠道微生物群的作用。通过i.p.葡萄糖和胰岛素耐量试验评估葡萄糖稳态。与WT小鼠相比，缺乏ANGPTL4的小鼠体重增加、内脏脂肪组织质量、内脏脂肪组织脂蛋白脂肪酶活性和内脏脂肪组织炎症增加。然而，他们也出乎意料地显著改善了葡萄糖耐量，并伴有胰岛素水平升高。ANGPTL4的缺失不影响离体胰岛中葡萄糖刺激的胰岛素分泌。由于肠道微生物群已被认为影响胰岛素分泌，并且ANGPTL4已被提出将肠道微生物群与宿主代谢联系起来，因此我们假设肠道微生物群的潜在作用。Angptl4−/−小鼠和WT小鼠的肠道菌群组成有显著差异。有趣的是，使用抗生素抑制肠道微生物群在很大程度上消除了WT和Angptl4 - / -小鼠之间葡萄糖耐量和胰岛素水平的差异。尽管增加内脏脂肪量，ANGPTL4的失活可以改善葡萄糖耐量，至少部分是通过肠道微生物依赖的机制。本文的在线版本（10.1007/s00125-018-4583-5）包含同行评审但未经编辑的补充材料，授权用户可使用。
Angiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in Angptl4−/− mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity. We chronically fed wild-type (WT) and Angptl4−/− mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests. Mice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between Angptl4−/− mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and Angptl4−/− mice. Despite increasing visceral fat mass, inactivation of ANGPTL4 improves glucose tolerance, at least partly via a gut microbiota-dependent mechanism. The online version of this article (10.1007/s00125-018-4583-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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综合基因组分析暗示有限的外周脂肪储存能力在人类胰岛素抵抗的发病机理中。
影响因子：
30.8
作者：
Lotta LA;Gulati P;Day FR;Payne F;Ongen H;van de Bunt M;Gaulton KJ;Eicher JD;Sharp SJ;Luan J;De Lucia Rolfe E;Stewart ID;Wheeler E;Willems SM;Adams C;Yaghootkar H;EPIC-InterAct Consortium;Cambridge FPLD1 Consortium;Forouhi NG;Khaw KT;Johnson AD;Semple RK;Frayling T;Perry JR;Dermitzakis E;McCarthy MI;Barroso I;Wareham NJ;Savage DB;Langenberg C;O'Rahilly S;Scott RA
通讯作者：
Scott RA
影响因子：
29
作者：
Lichtenstein L;Mattijssen F;de Wit NJ;Georgiadi A;Hooiveld GJ;van der Meer R;He Y;Qi L;Köster A;Tamsma JT;Tan NS;Müller M;Kersten S
通讯作者：
Kersten S
影响因子：
8.8
作者：
Kreznar JH;Keller MP;Traeger LL;Rabaglia ME;Schueler KL;Stapleton DS;Zhao W;Vivas EI;Yandell BS;Broman AT;Hagenbuch B;Attie AD;Rey FE
通讯作者：
Rey FE
影响因子：
4.5
作者：
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通讯作者：
Adeli, Khosrow
影响因子：
6.5
作者：
Janssen, Aafke W. F.;Houben, Tom;Kersten, Sander
通讯作者：
Kersten, Sander