Lactctococcus Lactis NZ3900 Expressed Oxyntomodulin As An Oral Delivery Inhibit Food Intake And Body Weight In Overweight Mice

Background:Obesity was defined as a disease by the World Health Organization(WHO)in 1948.Obesity rate is increasing all over the world these years.Obesity is associated with multiple morbidities,such as diabetes,hypertension,heart disease,sleep apnea,and cancer.Oxyntomodulin(OXM)is a 37-amino acid peptide secreted from the L cells.OXM injection with human can cause a significant reduction in weight and food-intake,as well as an increase in energy expenditure.But there are some inevitable defects of peptides drugs.On the one hand,the cost of synthesizing peptide drugs is expensive.On the other hand,injection is the only way to administer peptides,with a short half-life in vivo which is not inconvenience for patients.Therefore,this makes the delivery system more urgent to express OXM in vivo.As a probiotics,Lactococcus lactis(L.lactis)is GRAS(generally recognized as safe)and finds in the human gut.There are quite a few papers focus on the therapy of intestinal inflammation with Lactococcus lactis.In order To deliver OXM to the small intestine,we engineered food-grade strains of L.lactis to produce and secrete human OXM.We constructed OXM in L.lactis NZ3900(named as NZ3900-OXM)then analyzed the expression of OXM with Western-blot.The expression of recombinant OXM from the OXM-transformed L.lactis reached a maximum at 5 h after the induction.After that,we established diet induced obesity(DIO)model with high fat diet and divided the DIO mice into two groups,oral administration of OXM-transformed L.lactis(NZ3900-OXM)and NZ3900-V.We detected the food-intake,body weight,serum lipid and blood glucose to verify the therapeutic effect of OXM-transformed L.lactis.After 8 weeks of administration,OXM-expressing L.lactis can significantly reduce body weight,food intake and triglyceride of DIO mice.Interestingly,the fasting glucose of not only NZ3900-OXM but also NZ3900-V group returned to normal levels.To clarify whether OXM-transformed L.lastis have the same impact on db/db mice,we intragastric administration of NZ3900-OXM and NZ3900-V into db/db mice.After three weeks of administration,the body weight of NZ3900-OXM group remains unchanged.OXM-expressing L.lactis restores blood glucose and the plasma lipid of db/db mice.These results strongly suggest that OXM-expressing L.lactis can reduce food intake,plasma lipid and return blood glucose to normal in DIO mice and db/db mice.It is expected that OXM-expressing L.lactis can potentially used as a new type drugs to treat obesity and type 2 diabetes.