A Multi Omics Analysis of Modulation in Lipid Metabolism By glycerol Monolaurate in High-Fat Diet-Fed Mice
Author:Zhao Min Jie
Supervisor:feng feng qin
Recently,with the significant change of dietary structure,the intake proportion of high-fat food significantly increased,and lipid metabolism disorders(which is featured by hyperlipidaemia,excessive accumulation of visceral fat,obesity and et al.)induced by high-fat diet(HFD)has been one of the global scientific problems that need to be solved urgently.Glycerol monolaurate(GML),naturally existing in coconut oil,breast milk and palmetto,is a widely consumed food emulsifier with antibacterial and antiviral properties.In the previous studies,we found that dietary supplementation with 150 mg/kg GML significantly affected lipid metabolism and gut microbiota in low-fat dietfed mice.However,whether the same effects still exist upon HFD feeding is unknown.In the present study,we used a multi-omics(microbiome,metabolome and transcriptome)correlation study to explore the regulation of lipid metabolism induced by dietary GML supplementation in HFD-fed mice and the related mechanism.The main results are as follows:1.The regulation of lipid metabolism by low-dose GML supplementation depended on its dosage.150 mg/kg GML supplementation significantly increased the body weight,total body weight gain and epididymal fat pad weight in HFD-fed mice.300 and 450 mg/kg GML supplementation had no significant effect on body weight and toatal body weight gain in HFD-fed mice,but significantly improved hepatic lipid deposition and epididymal adipocyte hypertrophy.Low-dose GML supplementation significantly modulated insulin resisitance and systemic inflammation upon HFDfeeding.Additionally,dietary 300 and 450 mg/kg GML supplementation can regulate lipid metabolism and cholesterol synthesis by inhibiting hepatic PPARγ signaling pathway.2.The results of 16 S rRNA indicated that dietary GML supplementation affected gut microbiota in HFD-fed mice.Diet supplemented with 450 mg/kg GML significantly increased the abundance of Akkermansia,Bifidobacterium and Lactobacillus,which were positively correlated with the GML-induced metabolic modulation.And 450 mg/kg GML significantly reduced the abundance of Escherichia coli,which was correlated with the reduced serum LPS level and improved systemic inflammation.3.High-dose(800,1200 and 1600 mg/kg)GML supplementation has the similar effects on lipid metabolism regulation as low-dose GML supplementation,and 1600 mg/kg GML had the most significant effects.1600 mg/kg GML significantly reduced body weight,body fat rate,visceral fat deposition and improved hyperlipidemia in HFD-fed mice.In lipid metabolism,1600 mg/kg GML significantly inhibited PPARγ signaling pathway.In glucose metabolism,1600 mg/kg GML significant upregulated the glycolysis pathway and downregulted the gluconeogenesis patyway to maintain serum glucose level and improve insulin resistance.Furthermore,1600 mg/kg GML significantly reduced serum TNF-α,IL-6,LPS and LBP levels,modulated systemic inflammation and improved infiltration of hepatic macrophages.4.Dietary 1600 mg/kg GML supplementation significantly modulated HFDinduced gut microbiota dysbiosis and increased diversity of gut microbiota.The significantly increased abundance of Bacteroides,Dorea and Eggerthella(genus level)which were positively correlated with obesity were observed in 1600 mg/kg GMLsupplemented HFD-fed mice.And 1600 mg/kg GML selectively increased the abundance of Bifidobacterium(genus level)and Bifidobacterium pseudolongum(species level),which showed significantly positive correlation with the modulation of lipid metabolism induced by 1600 mg/kg GML supplementation.5.Antibiotic treatment abolished all the GML-mediated metabolic improvements,which confirmed that the improvements induced by GML supplementation in lipid metabolism disorders,insulin resistant and systemic inflammation depended on gut microbiota.GML was firstly reported to alleviate metabolic disorders caused by HFDfeeding based on its regulation of gut microbiota.6.A multi-omics(microbiome,metabolome and transcriptome)correlation study showed that GML significantly modulated glycerophospholipid metabolism,especially the level of serum lysophosphatidylcholine(LPC)18:0 which were strongly correlated with the metabolic improvements induced by GML.Our results indicated that GML can regulate lipid metabolism in HFD-fed mice by targeting the gut microbiota,Bifidobacterium pseudolongum is the characteristic gut microbes in response to the regulation of GML,and LPC(18:0)is the characteristic serum metabolite in response to the regulation of GML.