Gut Microbiota Mediates The Improvement Of Body Weight In Simple Obese Mice With GLP-1 Receptor Agonist

ObjectiveGlucagon-like peptide-1(GLP-1)is an insulinotropic peptide produced by intestinal L cells.In addition to controlling blood glucose level,GLP-1 can also delay postprandial gastric emptying,reduce appetite,promote glycogen synthesis in liver,muscle and adipose tissue,and inhibit energy intake.However,GLP-1 can be rapidly digested by dipeptidyl peptidase-4(DPP-4).In animal experiments,liraglutide,a GLP-1 receptor agonist(GLP-1RA),can reduce the blood glucose level of GK rats and other diabetic animal models by changing the structure of intestinal flora.However,independent of blood glucose levels,there are few studies on whether or how it can act on the intestinal microbiota to interfere with the body weight and lipid profile in animal models of simple obesity or overweight alone.The purpose of this study was to explore how liraglutide acts on the intestinal microbiota to regulate the body weight and lipid profile of simple obesity model mice induced by high-fat diet.MethodsMale C57BL/6 mice(4 weeks old)were randomly divided into normal control group(NC group,n=8)and high-fat diet group(HFD group,n=16).The mice in NC group were fed with standard diet,while HFD group mice were fed with high-fat diet to induce obesity.After the obesity model was successfully constructed,HFD group was divided into HFD group(HFD + normal saline,n=8)and HL group(HFD +liraglutide,n=8),and the same amount of saline or liraglutide were injected intraperitoneally.Body weight was monitored every two weeks.Eleven weeks after administration,intraperitoneal insulin tolerance test(IPITT)were performed.At the12 th week,blood samples were collected to detect blood lipid profile,and feces of mice were collected for intestinal microflora sequencing.Results(1)The results of body weight and metabolic indexes showed that: compared with the NC group,the body weight,total cholesterol(TC),low density lipoprotein(LDL)content of HFD group were significantly increased(P<0.05);Compared with HFD group,the HL group had significantly lower body weight,TG,TC and LDL contents,in which the differences of weight,TC and LDL were statistically significant(P<0.05)。(2)No significant changes in fasting blood glucose were observed among the three groups of mice,and no hypoglycemia occurred during the experiment.IPITT results showed that AUC of HL group was < NC group < HFD group,and the difference between HL group and HFD group was statistically significant(P<0.05).(3)The results of intestinal microflora sequencing showed that: compared with NC group,the diversity and abundance of microflora in HFD group decreased,the proportion of Firmicutes increased,the proportion of Bacteroides decreased,the ratio of Firmicutes/Bacteroides(F/B)increased;the abundance of the anti-obesity bacteria,such as Odoribacter,Akkermansia,Lactobacillius,Oscillospira and Parabaceroids,was decreased,and the harmful bacteria such as Shigela,AF12,Prevotella were enriched.Compared with HFD group,the intestinal microbial diversity and abundance of HL group were increased significantly,the relative abundance of Bacteroides increased,the relative abundance of Firmicutes decreased,and the ratio of F/B decreased,the proportion of anti-obesity bacteria increased,the proportion of harmful bacteria decreased,and the proportion of anti-inflammatory bacteria such as Sutterella,Butyricimonas and Mucispirillum increased.(4)Species composition difference analysis showed that Verrucomicrobia,Verrucomicrobiaes,Verrucomicrobiaceae,and Akkermansia in the feces of HL group mice had relatively high LDA values,suggesting that these groups could be used as the marker species of HL group.(5)At the level of microflora analysis,Akkermansia＿muciniphila showed the largest change in the proportion of the whole strain,with 25.13% in NC group,1.90%in HFD group,and 33.18% in HL group,which was nearly 18 times of HFD group.(6)Spearman correlation analysis showed that Bifidobacterium,Allobacillus,Ruminococcus and Aquabacterium were negatively correlated with body weight and blood lipid(including TC,TG and LDL)(P<0.05);Akkermansia was negatively correlated with TC and LDL(P<0.05);AF12,Shigella,Ruminococcus and Xenorhabdus were positively correlated with body weight and blood lipid(P<0.05).ConclusionLiraglutide significantly improved obesity induced by HFD in mice,and reduced body weight and lipid profile,with a corresponding increase in insulin sensitivity.Liraglutide changed the intestinal microflora of obese mice,reversed the changes in the structure and distribution of the microflora damaged by high-fat diet,and made the structure of the microflora of obese mice return to normal.Liraglutide mediated weight and lipid reduction in obese mice is partly due to structural changes of intestinal microorganisms associated with increased abundance of Akkermansia.GLP-1RA intervention is an important way to reverse obesity induced by high-fat diet,and its mechanism is closely related to the regulation of intestinal microbiota.