Ruiqing Liu1,2, Shuaihua Qiao3, Weisong Shen4, Yue Liu5, Yun Lu2, Liangyu Huang1, Zhen Guo1, Jianfeng Gong1, Guanghou Shui6, Yi Li1, Weiming Zhu1. 1. Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China. 2. Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, PR China. 3. Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China. 4. Department of Gastroenterological Surgery, Peking University People's Hospital. 5. State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Drum Tower Hospital, Model Animal Research Center, Nanjing University, Nanjing, China. 6. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, People's Republic of China; University of Chinese Academy of Sciences, Beijing, China.
Abstract
ACKGROUND AND AIMS: The aim of this study was to investigate the metabolic profile of mesenteric adipocytes and the correlations between key metabolic changes and local inflammation in the context of CD. METHODS: Metabolic dysfunction was shown to be regulated by fatty acid desaturase-2 (FADS2) through metabolomics and functional analyses of mesenteric adipose tissue biopsies and primary mesenteric adipocytes isolated from surgical specimens collected from CD patients and control subjects. FADS2 was overexpressed in vitro and in vivo using a lentiviral vector and an adeno-associated virus (AAV), respectively. The interaction between mesenteric adipocytes and inflammation responses was evaluated by establishing a cell coculture system and an FADS2-AAV treated animal model. 3T3-L1 cells were used to elucidate the mechanism underlying FADS2 deregulation. RESULTS: We observed significant changes in the levels of metabolites involved in the multi-step synthesis of long-chain polyunsaturated fatty acids (PUFAs). Gas chromatography analysis revealed impaired desaturation fluxes towards the n-6 and n-3 pathways, which are associated with reduced FADS2 activity in human mesentery tissue. Decreased FADS2 expression at both mRNA and protein levels was confirmed in surgical specimens. The restoration of FADS2 expression, which allows for the endogenous conversion of n-3 fatty acids into proresolving lipid mediators, resulted in a significant reduction in proinflammatory macrophage infiltration and attenuated expression of inflammatory cytokines or adipokines. CONCLUSIONS: These findings indicate that impaired fatty acid desaturation and lipid mediator imbalance within mesenteric adipose tissue contributes to chronic inflammation in CD. The therapeutic role of FADS2 may lead to improved CD treatment.
ACKGROUND AND AIMS: The aim of this study was to investigate the metabolic profile of mesenteric adipocytes and the correlations between key metabolic changes and local inflammation in the context of CD. METHODS:Metabolic dysfunction was shown to be regulated by fatty acid desaturase-2 (FADS2) through metabolomics and functional analyses of mesenteric adipose tissue biopsies and primary mesenteric adipocytes isolated from surgical specimens collected from CDpatients and control subjects. FADS2 was overexpressed in vitro and in vivo using a lentiviral vector and an adeno-associated virus (AAV), respectively. The interaction between mesenteric adipocytes and inflammation responses was evaluated by establishing a cell coculture system and an FADS2-AAV treated animal model. 3T3-L1 cells were used to elucidate the mechanism underlying FADS2 deregulation. RESULTS: We observed significant changes in the levels of metabolites involved in the multi-step synthesis of long-chain polyunsaturated fatty acids (PUFAs). Gas chromatography analysis revealed impaired desaturation fluxes towards the n-6 and n-3 pathways, which are associated with reduced FADS2 activity in human mesentery tissue. Decreased FADS2 expression at both mRNA and protein levels was confirmed in surgical specimens. The restoration of FADS2 expression, which allows for the endogenous conversion of n-3 fatty acids into proresolving lipid mediators, resulted in a significant reduction in proinflammatory macrophage infiltration and attenuated expression of inflammatory cytokines or adipokines. CONCLUSIONS: These findings indicate that impaired fatty acid desaturation and lipid mediator imbalance within mesenteric adipose tissue contributes to chronic inflammation in CD. The therapeutic role of FADS2 may lead to improved CD treatment.