Effect And Mechanism Of Fibroblast Growth Factor 21 On The Pathogenesis Of Acute Colitis

Inflammatory bowel diseases(IBDs)are chronic relapsing disorders of the gastrointestinal tract that are characterized pathologically by intestinal inflammation and epithelial injury.Fibroblast growth factor 21(FGF21)is a novel metabolic regulator in glucose and lipid metabolism.Recent studies showed that FGF21 is also induced by inflammatory stimuli.However,its role in inflammatory bowel disease(IBD)has not been examined.We sought to determine the role of FGF21 in IBD and to discern underlying mechanisms.Methods:1.Serum levels of FGF21 in inflammatory bowel disease patients were measured.2.Experimental IBD model was induced by adding 2.5%(wt/vol)dextran sulfate sodium(DSS)into drinking water for 3,5 and 7 days,respectively,in FGF21 knockout(KO)and wide type(WT)mice.Mouse colon tissues were analyzed for colitis severity and inflammatory cell infiltration.FGF21 and inflammatory makers were determined in serum and tissues samples.The T84 intestinal epithelial cell line was used for additional in vitro studies.3.Mice were given 2.5% dextran sulfate sodium(DSS)ad libitum for 7 days in drinking water to induce experimental colitis.The role of FGF21 was investigated using antibody neutralization or knockout(KO)mice.Lipolysis index and adipose intracellular activation of lipolytic enzymes were determined.In addition,fully differentiated 3T3-L1 cells were pretreated with or without IL-6,followed by recombinant human FGF21(rhFGF21)treatment,lipolysis was assessed by measuring glycerol concentration in culture media.Result:1.Mean serum FGF21 concentrations were significantly increased in inflammatory bowel disease patients.2.In WT mice treated with DSS induced an elevation in serum FGF21 and a significant body weight loss in a time dependent manner.Gene expression studies showed that liver and epididymal white adipose tissues were the major sources of circulation FGF21,and intestinal tissue can express FGF receptor and ?-klotho.Surprisingly,the body weight loss and colitis severity were significantly attenuated in FGF21 KO mice.Further analysis showed that FGF21 KO mice had less colon shortening,histological damage,less neutrophil infiltration compared to WT mice.FGF21 deficiency decreased DSS treatment-increased serum concentrations of IL-6,TNF-? and IL-1? and their mRNA levels in colon tissues.Colonic epithelial cell proliferation,examined by BrdU staining,was increased in the KO mice.DSS treatment caused a decrease in epithelial cell proliferation and Paneth and Goblet cell numbers in WT mice,which were attenuated in the KO mice.Importantly,FGF21 depletion dramatically increased signal transducer and activator of transcription(STAT)activation in intestinal epithelial cells,along with a decreased suppressor of cytokine signaling-3(Socs3)expression.FGF21 pretreatment inhibited IL6-induced STAT3 phosphorylation in human intestine epithelial T84 cells.3.Experimental colitis markedly decreased eWAT/body weight ratio and increased serum concentrations of free fatty acid(FFA)and glycerol,indicating increased adipose tissue lipolysis in animals with colitis.eWAT intracellular lipolytic enzyme expression/activation was significantly increased.These alterations were significantly attenuated in FGF21 KO mice and by circulating FGF21 neutralization.Moreover,DSS treatment markedly increased serum IL-6 and FGF21 levels.IL-6 pretreatment was necessary for he the stimulatory effect of FGF21 on adipose lipolysis in 3T3-L1 cells.Conclusion:1.Circulating levels of FGF21 were increased in inflammatory bowel disease patients and acute colitis in mice.FGF21 deficiency attenuated DSS induced acute colitis,which is likely mediated by the inhibitory effect of FGF21 on IL-6-induced-STAT activation in intestinal epithelial cells.2.Our results demonstrate that experimental colitis induces eWAT lipolysis via an IL-6/FGF21-mediated signaling pathway.To our knowledge,this is the first study to elucidate the role of FGF21 in the inflammatory bowel disease.We found that in the case of inflammatory bowel disease,FGF21 play a different role in different tissues and organs.FGF21 will increase the intestinal inflammatory response and injury in the intestinal tissue,but will induce adipose lipolysis to supplement the body's energy needs in adipose tissue.According to FGF21 plays a different role in the regulation of different tissues and organs.Targeting FGF21 pathway may be useful in the design of novel strategies for treatment/prevention of inflammatory bowel disease.