Disturbance of Fatty Acid Desaturation Mediated by FADS2 in Mesenteric Adipocytes Contributes to Chronic Inflammation of Crohn's Disease

Abstract

Background and Aims: Mesenteric fat accumulation as observed in Crohn's disease (CD) is linked to chronic gut inflammation. The aim of this study is to investigate the metabolic profile of mesenteric adipocytes and the interactions between key metabolic alterations and local inflammation in the context of CD. Methods: Metabolic dysfunction regulated by Fatty Acid Desaturase-2 (FADS2) was identified by performing metabolomics and functional analyses in mesenteric adipose tissue biopsies and primary mesenteric adipocytes isolated from surgical specimens from patients with CD and control subjects. FADS2 was overexpressed in vitro with a lentiviral vector and an adeno-associated virus (AAV) in vivo. The interaction of mesenteric adipocytes and inflammation response was evaluated by establishing a cell coculture system and a FADS2-AAV treated animal model. 3T3-L1 cell was used to determine the mechanism underlying FADS2 deregulation. Results: We identified significantly changed metabolites involved in the multi-step synthesis of long-chain polyunsaturated fatty acids (PUFAs). Gas chromatography analysis revealed impaired desaturation fluxes toward the n-6 and n-3 pathways linking with reduced FADS2 activity in human mesentery. Decreased expression of FADS2 at both mRNA and protein level were confirmed in surgical specimens. Restoration of FADS2, which allows the endogenous conversion of n-3 fatty acids into pro-resolving lipid mediators, produced a significant reduction in pro-inflammation macrophage infiltration and attenuated expression of inflammatory cytokines or adipokines. Conclusions: These findings indicate that impaired fatty acid desaturation and unbalanced lipid mediators within mesenteric adipose contribute to chronic inflammation of CD. The therapeutic role of FADS2 may lead to improved treatment. Funding: This study was supported by National Natural Science Foundation of China [81770556]. Declaration of Interest: Authors confirm that there is no conflict of interest to declare. Ethical Approval: This study has been approved by the Ethics Committee of Jinling Hospital (Control ID: NZGKJ-063). All enrolled patients were consented.