Cellular & Systems Neurobiology, Systems Biology Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
INSERM U1016, Cochin Institute, Paris, France; CNRS UMR 8104, Paris, France; University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
Free Radic Biol Med. 2018 Jan;114:122-130. doi: 10.1016/j.freeradbiomed.2017.09.021. Epub 2017 Sep 25.
Down syndrome (DS) is caused by the trisomy of human chromosome 21 and is the most common genetic cause of intellectual disability. In addition to the intellectual deficiencies and physical anomalies, DS individuals present a higher prevalence of obesity and subsequent metabolic disorders than healthy adults. There is increasing evidence from both clinical and experimental studies indicating the association of visceral obesity with a pro-inflammatory status and recent studies have reported that obese people with DS suffer from low-grade systemic inflammation. However, the link between adiposity and inflammation has not been explored in DS. Here we used Ts65Dn mice, a validated DS mouse model, for the study of obesity-related inflammatory markers. Ts65Dn mice presented increased energy intake, and a positive energy balance leading to increased adiposity (fat mass per body weight), but did not show overweight, which only was apparent upon high fat diet induced obesity. Trisomic mice also had fasting hyperglycemia and hypoinsulinemia, and normal incretin levels. Those trisomy-associated changes were accompanied by reduced ghrelin plasma levels and slightly but not significantly increased leptin levels. Upon a glucose load, Ts65Dn mice showed normal increase of incretins accompanied by over-responses of leptin and resistin, while maintaining the hyperglycemic and hypoinsulinemic phenotype. These changes in the adipoinsular axis were accompanied by increased plasma levels of inflammatory biomarkers previously correlated with obesity galectin-3 and HSP72, and reduced IL-6. Taken together, these results suggest that increased adiposity, and pro-inflammatory adipokines leading to low-grade inflammation are important players in the propensity to obesity in DS. We conclude that DS would be a case of impaired metabolic-inflammatory axis.
唐氏综合征（DS）是由人类 21 号染色体三体引起的，是智力障碍最常见的遗传原因。除了智力缺陷和身体异常外，DS 个体比健康成年人更容易出现肥胖和随后的代谢紊乱。越来越多的临床和实验研究证据表明，内脏肥胖与促炎状态有关，最近的研究报告称，患有 DS 的肥胖者患有低度全身炎症。然而，在 DS 中，肥胖与炎症之间的联系尚未得到探索。在这里，我们使用 Ts65Dn 小鼠，一种经过验证的 DS 小鼠模型，研究与肥胖相关的炎症标志物。Ts65Dn 小鼠表现出能量摄入增加，能量正平衡导致脂肪量增加（相对于体重），但没有超重，只有在高脂肪饮食诱导肥胖时才会出现超重。三体小鼠还表现出空腹高血糖和胰岛素血症，以及正常的肠降血糖素水平。这些与三体相关的变化伴随着生长激素释放肽（ghrelin）血浆水平降低和瘦素水平略有但无统计学意义升高。在葡萄糖负荷下，Ts65Dn 小鼠表现出正常的肠降血糖素增加，同时伴随着瘦素和抵抗素的过度反应，而保持高血糖和低胰岛素血症表型。这些脂肪-胰岛轴的变化伴随着与肥胖相关的炎症生物标志物的血浆水平升高，如半乳糖凝集素-3 和 HSP72，以及白细胞介素-6 水平降低。综上所述，这些结果表明，肥胖增加和促炎脂肪因子导致低度炎症是 DS 肥胖倾向的重要因素。我们得出结论，DS 是代谢-炎症轴受损的一个例子。
