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The Function And Mechanism Of N-acyl Amino Acid Analogues In Regulating Energy Metabolism Of The Adipose Tissue

Posted on:2024-05-19Degree:MasterType:Thesis
Country:ChinaCandidate:W X GuoFull Text:PDF
GTID:2544307070961989Subject:Biochemistry and Molecular Biology
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Currently,obesity has become an epidemic disease.Obesity rates are steadily increasing around the world.So researchers are working on ways to treat obesity.Studies have shown that N acyl amino acids can promote mice to resist obesity induced by high fat diet and improve metabolic disorders.In addition,a study published in Cell journal in2016 pointed out that PM20D1,as a rate-limiting enzyme regulating the synthesis and decomposition of N-acyl amino acids in vivo,can regulate energy metabolism by regulating N-acyl amino acids in vivo.Because N acyl amino acids are affected by their substrates,products and enzymes,their stability is poor in vivo.In order to enhance the stability of N acyl amino acids in vivo,we constructed an analog of N acyl amino acids--CP-L3862,and explored its influence on obesity and its mechanism.In this study,Intraperitoneal injection of CP-L3862 improved high-fat diet-induced obesity,improved insulin sensitivity and glucose tolerance,and increased energy expenditure and adaptive thermogenic production in mice.In addition,CP-L3862 treatment could not induce Ucp1 expression,but up-regulated Ant expression and enhanced proton uncoupling ability.At the same time,CP-L3862 was found to bind to HIF-3α by drug binding assay,and CP-L3862 was found to enhance the transcriptional activation of HIF-3α by double luciferin reporter assay and target gene expression detection.In addition,knockdown of Hif-3α in adipocytes down-regulated Ant expression,and CP-L3862 treatment did not affect Ant expression changes.By double luciferase assay and Ch IP assay,we found that HIF-3α up-regulates Ant expression by binding with HRE2.At the same time,we also found that CP-L3862 enhanced creatine ineffective cycling gene expression and creatine kinase activity in vitro and in vivo.Taken together,these results reveal the functional role of CP-L3862 in promoting thermogenesis,which depends on the increase of HIF-3αactivity and the enhancement of creatine ineffective circulation.Therefore,our study reveals the potential mechanism of CP-L3862,an N-acyl amino acid analogue,against obesity.In conclusion,the potential mechanism of CP-L3862,the N-acyl amino acid analogues,against obesity induced by high fat diet was discovered,and the important role of HIF-3α in enhancing energy metabolism and thermogenesis was revealed.The results of this study will provide a basis for the future treatment of obesity with N-acyl amino acid analogues,and provide an important basis for the construction of HIF-3αagonists.
Keywords/Search Tags:obesity, adipose tissue, N acyl amino acids, hypoxia-inducible factor-3, proton uncoupling, creatine ineffective cycle
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