The Effect Of Fatty Acid Synthase Inhibition On The Blood Glucose,Oxidation And Metabolism Of Obesity Induced By High-fat And High-sugar Diets Respecitively

Obesity has become a pandemic.It is well known that a sedentary life style,especially high energy diet,are important pro-obese factors.Excessive intake of high-energy diets is an important cause of most obesity.Overweight and impaired glucose tolerance are two key characteristics of diet-induced obesity.Dietary fat intake regulates not only the expression of lipid metabolism-related genes through a variety of molecular pathways,but also the signal transduction of hormones related to appetite.In addition,these molecular pathways involved in lipid metabolism are also related to chronic inflammation and insulin resistance.However,cases of high-sugar diets used in metabolic syndrome are relatively rare.Fatty acid synthase(FASN)is a key enzyme for the de novo synthesis of fatty acids,and an enzyme necessary for the synthesis of fats from sugars in the body.It can be used as a breakthrough to study the effects of different diets with different energy substances on obese mice.In this project,mice are respectively fed with high sugar diet and high fat diet but the same energy density to study the obesity caused by different dynamophore(refined sugar or fat)when the dietary energy density is constant,and to explore its phenotype and metabolism.The similarities and differences with oxidative stress are expected to provide another way of thinking and possibility for regulating obesity and its related metabolic syndrome by improving dietary structure.The main findings of this article are as follows:(1)Different high energy diets with the same energy density but different fat-sugar ratios are used in the study.We found that mice with similar obesity phenotypes induced by high fat diet(HFD)and high sugar diet(HSD)have significant differences in intestinal microflora and the progress of body weight and blood glucose disorder.C57BL/6J mice were used as experimental subjects.When fed with refined sugar and fat with different energy supply ratios but with the same energy density for 11 weeks,the mice in each group were obese and had blood glucose disorders,but the HFD group was overweight at 6 weeks 20% and there is a significant difference between fasting blood glucose and the NC group,while the MFSD group and the HSD group only have significant decrease in glucose tolerance.In addition,different diets induced different models of obesity-related gut microbiota in obese mice.(2)Construct a fat metabolism inhibition system and screen a novel fatty acid synthase inhibitor.In this study,we obtained a new small molecule inhibitor PFI09 which binds to KRdomain of FASN through structure-based virtual screening.The chemically stable analog of PFI09,MFI03,which reduces the proliferation of PC3 cells both in vitro and in vivo,without toxicity to mice.In summary,our data suggest that MFI03 is an effective FASN inhibitor and a promising antineoplastic drug candidate.(3)FASN inhibitors interfere with inflammation and oxidative stress caused by HSD.FASN is an enzyme that is necessary to synthesize lipids from sugar in the body.When its function is inhibited,mice in the HFD group rather than mice in the HFD group are affected significantly.Compared to mice in the HSD control group,mice with intraperitoneal injection of cerulenin and MFI03 have improved in weight,fat mass,liver mass,inflammation and oxidation.(4)FASN inhibitors interfer with metabolic disorders by HSD.FASN inhibition effect the synthesis of endogenous fatty acids,thereby reducing the total lipid content and triglyceride(TG)levels in the mice liver of HSD group.The non-targeted metabolome analysis also show that inhibiting FASN regulates liver metabolism disorder in obese mice feeding of high-sugar diet by various metabolc pathways such as glycerophospholipid metabolism,propionic acid metabolism,and histidine metabolism.In summary,this study screened and obtained stable and effective novel small molecule inhibitors of FASN,and found that inhibiting FASN activity can effectively improve obesity and metabolic disorders caused by HSD.This provides a theoretical basis for regulating obesity and its related metabolic syndrome by improving dietary structure.