Jacobsen Mette J, Mentzel Caroline M Junker, Olesen Ann Sofie, Huby Thierry, Jørgensen Claus B, Barrès Romain, Fredholm Merete, Simar David
Animal Genetics, Department of Veterinary Clinical and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark.
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S 1166, Integrative Biology of Atherosclerosis Team, 75013 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, 75013 Paris, France.
J Diabetes Res. 2016;2016:8539057. doi: 10.1155/2016/8539057. Epub 2015 Dec 21.
Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity.
肥胖与导致胰岛素抵抗的免疫紊乱有关。表观遗传机制可以控制免疫功能，并且与代谢并发症相关，尽管其对胰岛素抵抗的作用仍不清楚。在本研究中，我们在猪肥胖模型中研究了代谢功能障碍与免疫改变之间的联系以及白细胞中的表观遗传特征。通过流式细胞术确定循环白细胞的整体DNA甲基化、脂肪组织白细胞转运和巨噬细胞极化。通过定量代谢物以及与肥胖和炎症相关的基因表达水平，进一步表征脂肪组织炎症和代谢功能。在此我们表明，肥胖猪的内脏脂肪垫更大、循环低密度脂蛋白胆固醇水平更高且葡萄糖耐量受损。这些变化与代谢受损、巨噬细胞持续浸润以及脂肪组织炎症增加同时出现。这些免疫改变与B细胞和T细胞中的整体DNA高甲基化有关。我们的结果为免疫细胞表观遗传学对肥胖中观察到的免疫紊乱可能产生的作用提供了新的见解。循环淋巴细胞转录组和表观遗传特征的巨大变化强化了这样一种概念，即表观遗传过程参与了肥胖中免疫细胞激活增加和代谢功能受损。
