| Obesity is prone to cause a variety of chronic metabolic diseases,and the rapid increase in the obese population has put more and more pressure on people over the years.The lipase inhibitors work in the intestine and no side effects on the central nervous system has become a hot topic in recent years.This paper has comprehensively studied the mechanism of anti-obesity drugs inhibition at the molecular level,cell level and zoological models.First,five lipase inhibitors were screened from more than 50 compounds:furoic acid,catechin,oxalic acid,salicylic acid,and glycolic acid(IC50 were 2.2,13.4,15.8,24.6,and 27.9 mM,respectively).Inhibition mechanism model,inhibition type model,inactivation mechanical model,spectroscopic analysis and molecular dynamics simulation were established,and the relationship and effect of each inhibitor on lipase inhibition were discussed at multiple levels and in various aspects.According to the preliminary study,a relatively safe and efficient lipase inhibitor active substance-FBT was screened from natural products with an IC50 value of 1.02?g/mL.At the same time,the extraction process was relatively simple and the method was quick and simple.The total yield was 1.34%.From the perspective of enzyme kinetics and spectroscopy,the mechanism of the inhibitory effect of FBT on lipase was studied.Further cell-level analysis for this study.Determined by MTT and oil red O,it was found that the average inhibition rate of FBT on 3T3-L1 preadipocyte proliferation and differentiation was 35.2%and 51.3%,respectively.FBT was not toxic and have no proapoptotic effect Adipocytes.Q-PCR and WB tests on the differentiation transcription factors PPAR-y and C/EBP-? have confirmed the inhibition of FBT on preadipocyte differentiation.Studied the inflammatory factors IL-6,TNF-?,IKK? genes of the mRNA and protein expression levels,it was found that FBT has a certain restrictive effect on the inflammatory response and can improve insulin resistance.FBT significantly reduces the mRNA and protein expression of genes related to adipogenesis and differentiation,and reduces the synthesis and promote of TG and TC,promoted the oxidation of fatty acids,indicating that the regulation of FBT on adipocytes is closely related to the regulation of AMPK pathway.Finally,based on a food-borne obese mouse model,it was found that the intervention of tea could significantly inhibit the increase in body weight and body fat rate,and it could inhibit insulin resistance and improve glucose tolerance,simultaneously it reduce peripheral renal fat volume and liver volume.The content of TG and TC in tissues and serum was reduced,and the total antioxidant capacity was improved.Oil red staining and scanning electron microscopy showed that lipid droplets and cell volume in adipose tissue were reduced,and vacuoles and fibrosis in the liver were improved,showed the hepatoprotective effect at the same time.Through the metabolomics analysis,it was found that FBT improves the transport of HDL in mice.It promotes the breakdown of cholesterol into bile acids,accelerates the beta oxidation of triglycerides in the body,and promotes the breakdown of fatty acids and the conversion of dag to PC and PE.The inhibition mechanism of FBT as an anti-obesity natural product drug was discussed,and it provided a theoretical basis for the screening and clinical treatment of lipase inhibitors for obesity related metabolic syndrome. |
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