We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs’ liver samples. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Molecular pathways related to CD8 + T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Transgenic effect increased the risk of metabolic disorders. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPR dn, hIAPP and PNPLA3 I148M. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy.
However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. 6Shanghai Key Laboratory of Children’s Digestion and Nutrition, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaĪnti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases.5Faculty of Medicine, University of Helsinki, Helsinki, Finland.4College of Animal Sciences & Technology, Huazhong Agricultural University, Wuhan, China.3The Ministry of Health Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.2Gembloux Agro-Bio Tech, University of Liège, Gembloux, Belgium.
1State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China.Kaiyi Zhang 1,2†, Cong Tao 1†, Jianping Xu 3†, Jinxue Ruan 1,4, Jihan Xia 1,5, Wenjuan Zhu 1, Leilei Xin 1, Huaqiong Ye 1, Ning Xie 1, Boce Xia 1, Chenxiao Li 1, Tianwen Wu 1, Yanfang Wang 1, Martine Schroyen 2, Xinhua Xiao 3*, Jiangao Fan 6* and Shulin Yang 1*