Effects Of Methionine Restriction On Glucose Metabolism In Obese Mice Induced By High-Fat Diet

Obesity is an important risk factor of type 2 diabetes mellitus.It is of great practical significance to study how to reduce insulin resistance and improve glucose metabolism through dietary means to prevent the occurrence of diabetes mellitus and prevent its further development.It has been found that methionine restriction?Methionine restriction,MR?can reduce blood glucose and improve insulin sensitivity.The aim of this study was to investigate the effects of MR on glucose metabolism in obese mice induced by high-fat diet and its possible regulatory mechanism under different time points and different energy intake levels.In this experiment,male C57BL/6J micewere randomly divided into two groups according to their body weight:control diet group?CON group,0.86%methionine+4%fat,n=30?and high fat diet group?HF group,0.86%methionine+20%fat,n=180?.Ten weeks later,120 mice which were successfully established the obesity model were randomly divided into 4 groups according to body weight:?1?high fat diet group?HF group,0.86%methionine+20%fat,n=30?;?2?high fat+methionine restricted diet group?HF+MR group,0.17%methionine+20%fat,n=30?;?3?control diet group?C*group,0.86%methionine+4%fat,n=30?;?4?control+methionine restricted diet group?C*+MR group,0.17%methionine+4%fat,n=30?.The samples were collected and analyzed at 8,16 and 24 weeks after the final grouping.Compared with HF group and C*group,HF+MR group and C*+MR group significantly decreased fasting blood glucose level,insulin resistance index?HOMA-IR?and body weight,and increased food intake and energy intake at all time points.At the 24^th week,HOMA-IR in C*+MR group was significantly lower than that in HF+MR group,but there was no significant difference in fasting blood glucose level,fasting insulin level and glucose tolerance between C*+MR group and HF+MR group.Compared with the HF group,the levels of hydrogen sulfide?H₂S?in plasma,pancreas,inguinal white adipose tissue?IWAT?and skeletal muscle were significantly increased in the HF+MR group at the16^th and 24^th week.In the C*+MR group,compared with the C*group,the level of H₂S in the pancreas increased significantly at 8^th week,the level of H₂S in IWAT increased significantly at the16^th and 24^th week,and the level of H₂S in skeletal muscle increased significantly at the 24^th week.The levels of H₂S in IWAT and skeletal muscle in the C*+MR group were higher than those in the HF+MR group at the 24^thh week.Plasma and skeletal adiponectin levels in the HF+MR group were significantly higher than those in the HF+MR group at the16^th and 24^th week.Adiponectin levels in the C*+MR group were higher than those in the HF+MR group at the 24^th week.Compared with HF group,HF+MR group,C*group and C*+MR group maintained the normal morphology of islet cells and improved the redox state of plasma and pancreas,and there was no significant difference in most of the indexes between the two MR groups at the24^th week.In pancreas,the mRNA expressions of endoplasmic reticulum stress-related genes Xbp-1,CHOP and IRE1?and apoptosis-promoting gene Bax were significantly down-regulated in HF+MR group,while the expressions of H₂S synthesis related gene CBS and CSE,anti-apoptosis gene Bcl-2 and insulin secretion related genes MafA and Pdx-1were up-regulated.At the 8^th week,the mRNA expressions of CBS,Bcl-2 and MafA and Pdx-1 were significantly up-regulated in C*+MR group compared with those in C*group.In IWAT,the gene expressions of CSE and DsbA-L were significantly increased in HF+MR group at the16^th and 24^th week compared with those in HF group.In skeletal muscle.compared with those in HF group,the mRNA expression levels of CSE,AdipoR1,glycolysis related genes?HK2,PFK and PKM?,mitochondrial related mtDNA copy number,TFAM and PGC-1?in HF+MR group were significantly increased at the16^th and 24^th week.Compared with those in HF group,the expressions of glycogen,GLUT4,AMPK,IRS-1,PI3K and Akt,and the phosphorylated protein levels of PI3K,Akt and GSK-3?in skeletal muscle of HF+MR group were increased at all time points.The expression levels of mTORC1,S6K1,Notch1 and STAT3 genes and mTORC1 protein were decreased.Most of the indexes showed no significantly difference between HF+MR group and C*+MR group.In conclusion,MR can protect pancreas and promote insulin secretion by improving endoplasmic reticulum stress and redox state of pancreas in obese mice induced by high-fat diet.Moreover,dietary MR increased the level of adiponectin by regulating the expression levels of H₂S and DsbA-L gene in IWAT and the level of H₂S in skeletal muscle,and then improved the uptake of glucose by skeletal muscle,glycogen synthesis,glycolysis and mitochondrial function.Therefore,the muscle glucose metabolism and IR were improved,and the steady state of blood glucose was maintained.In addition,the regulation of MR on glucose metabolism is sustainable and is not affected by energy intake.