Circulating FGF21 Levels In The Development And Progression Of Nafld And The Mechanisms Of Fgf21 In Improving Glucose Metabolism

Fibroblast growth factor 21(FGF21)can regulate various aspects in energy metabolism.Previous animal studies reported that FGF21 intervention can reduce weight,decrease blood glucose level and improve lipid profile.However,circulating levels of FGF21 are significantly increased in subjects with obesity,type 2 diabetes,non-alcoholic fatty liver disease(NAFLD),coronary heart disease and other metabolic-related diseases.This phenomenon suggests that excessive energy intake causes FGF21 resistance.It is not entirely figured out the patterns of FGF21 levels during the the development and progression of NAFLD,as well as how endogenous FGF21 improves glucose metabolism.This study investigated FGF21 level during the development and progression of NAFLD and the mechanism of FGF21 in improving systemic glucose metabolism.1.Circulating FGF21 levels in the Development and Progression of NAFLD.Objective: FGF21 levels were found to be elevated in NAFLD patients in our previous studies.Prospective study also found that serum FGF21 level was an independent predictor of NAFLD.Whether FGF21 is able to distinguish between simple hepatic steatosis and nonalcoholic steatohepatitis(NASH)is still not clear.In this part,we investigated and compared the level of FGF21 with cytokeratin 18(CK18)in the development and progression of NAFLD.Methods: We conducted both cross-sectional and longitudinal studies.808 subjects from a community of shanghai were followed up for 3 years.Baseline FGF21,CK18 fragment(CK18 M30)and total CK18(CK18 M65ED)levels were measured by ELISA.Results: 1.Baseline FGF21 level was an independent predictor of simple hepatic steatosis.2.Baseline CK18 levels including both M30 and M65 ED can not independently predict the occurrence of simple hepatic steatosis.However,CK18 M65 ED was an independent predictor of pregression to suspected NASH.3.Baseline CK18 M30 levels in patients who had remission of NAFLD during follow-up were significantly lower than those in patients who maintained NAFLD(84.74 U/L [53.26-135.79] vs.118.47 U/L [87.16-188.89],P = 0.012).Conclusion: FGF21 can be used for the early diagnosis of hepatic steatosis.Measurement of CK18 level can be helpful for predicting the prognosis NAFLD patients.FGF21 and CK18 have complementary value in the diagnosis and monitoring of NAFLD patients.The results also suggest that FGF21 may be involved in improving insulin resistance in the early stage of NAFLD.2.The Mechanisms of FGF21 in improving systemic glucose metabolism.Objective: In the first part of this study,it was found that FGF21 levels were elevated at the stage of simple steatosis in NAFLD patients and were not associated with hepatocellular inflammation and liver injury.Therefore,FGF21 may be involved in the regulation of systemic glucose metabolism under the circumstance of excessive energy intake during the early stage of NAFLD.Previous studies have reported that FGF21 can reduce body weight,decrease blood glucose level and improve lipid profile,suggesting that dipose tissue might be the main target tissue of FGF21.This part explores how FGF21 acts on adipose tissue to regulate systemic glucose metabolism.Methods: FGF21 knockout mice(FGF21 KO)model was used to investigate the effect of FGF21 on insulin resistance.The mice were treated with recombinant mouse FGF21 protein by osmotic pump.The role of ?klotho in FGF21 function of improving insulin resistance was studied using ?klotho adipose tissue specific knockout(Klb Adipo KO)mice model.The relationship between fat and FGF21 in regulating glucose metabolism was studied by fat transplantation.Results: 1.FGF21 KO mice and Klb Adipo KO mice showed significant insulin resistance,decreased glucose tolerance and reduced subcutaneous adipose tissue(SAT)volume after fed with high-fat diet(HFD).2.Treatment with physiological dose of recombinant mouse FGF21(rm FGF21)protein significantly increased the volume of SAT and improved insulin resistance.Transplantation of SAT of wild-type mice(WT)into FGF21 KO mice also improves glucose metabolism.3.However,treatment with rm FGF21 did not increase the the volume of SAT and not improve insulin resistance in Klb Adipo KO mice.4.FGF21 treatment significantly increased glucose uptake in cultured primary adipocytes derived from SAT of FGF21 KO mice.FGF21 significantly promoted the expression of PPAR? target genes and adiponectin in SAT and increase circulating adiponectin levels.FGF21 also induced macrophage polarization to the anti-inflammatory M2 cells in SAT.Conclusion: FGF21 is required for the accumulation of subcutaneous fat in diet-induced obesity.Increased endogenous FGF21 can regulate fat distribution and improve insulin resistance.This process requires the involvement of FGF21 co-receptor ?klotho.The mechanisms by which FGF21 improves systemic insulin resistance through the expansion of SAT may involve increased circulating adiponectin levels and decreased adipose tissue inflammation.