Wouters Kristiaan, Deleye Yann, Hannou Sarah A, Vanhoutte Jonathan, Maréchal Xavier, Coisne Augustin, Tagzirt Madjid, Derudas Bruno, Bouchaert Emmanuel, Duhem Christian, Vallez Emmanuelle, Schalkwijk Casper G, Pattou François, Montaigne David, Staels Bart, Paumelle Réjane
1 Université Lille 2, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
2 Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.
Diab Vasc Dis Res. 2017 Nov;14(6):516-524. doi: 10.1177/1479164117728012. Epub 2017 Sep 2.
The genomic CDKN2A/B locus, encoding p16 among others, is linked to an increased risk for cardiovascular disease and type 2 diabetes. Obesity is a risk factor for both cardiovascular disease and type 2 diabetes. p16 is a cell cycle regulator and tumour suppressor. Whether it plays a role in adipose tissue formation is unknown. p16 knock-down in 3T3/L1 preadipocytes or p16 deficiency in mouse embryonic fibroblasts enhanced adipogenesis, suggesting a role for p16 in adipose tissue formation. p16-deficient mice developed more epicardial adipose tissue in response to the adipogenic peroxisome proliferator activated receptor gamma agonist rosiglitazone. Additionally, adipose tissue around the aorta from p16-deficient mice displayed enhanced rosiglitazone-induced gene expression of adipogenic markers and stem cell antigen, a marker of bone marrow-derived precursor cells. Mice transplanted with p16-deficient bone marrow had more epicardial adipose tissue compared to controls when fed a high-fat diet. In humans, p16 gene expression was enriched in epicardial adipose tissue compared to other adipose tissue depots. Moreover, epicardial adipose tissue from obese humans displayed increased expression of stem cell antigen compared to lean controls, supporting a bone marrow origin of epicardial adipose tissue. These results show that p16 modulates epicardial adipose tissue development, providing a potential mechanistic link between the genetic association of the CDKN2A/B locus and cardiovascular disease risk.
基因组CDKN2A/B位点（其中包括编码p16）与心血管疾病和2型糖尿病风险增加有关。肥胖是心血管疾病和2型糖尿病的一个风险因素。p16是一种细胞周期调节因子和肿瘤抑制因子。它是否在脂肪组织形成中发挥作用尚不清楚。在3T3/L1前脂肪细胞中敲低p16或小鼠胚胎成纤维细胞中p16缺乏会增强脂肪生成，这表明p16在脂肪组织形成中发挥作用。p16缺陷小鼠对促脂肪生成的过氧化物酶体增殖物激活受体γ激动剂罗格列酮产生更多的心外膜脂肪组织。此外，p16缺陷小鼠主动脉周围的脂肪组织显示出罗格列酮诱导的脂肪生成标志物和干细胞抗原（骨髓来源前体细胞的标志物）基因表达增强。与对照组相比，喂食高脂饮食时移植了p16缺陷骨髓的小鼠有更多的心外膜脂肪组织。在人类中，与其他脂肪组织库相比，p16基因在心外膜脂肪组织中表达丰富。此外，与瘦对照组相比，肥胖人类的心外膜脂肪组织显示干细胞抗原表达增加，支持心外膜脂肪组织起源于骨髓。这些结果表明p16调节心外膜脂肪组织发育，为CDKN2A/B位点的遗传关联与心血管疾病风险之间提供了潜在的机制联系。
