| Insulin resistance means that insulin sensitivity of target tissue decreases,resulting in glucose utilization of tissue mediated by insulin declining,which is the early pathological mechanism of obesity and type 2 diabetes.Mitochondria are the key position for energy metabolism,so the alterations of mitochondrial quantity and morphology or metabolic disorder not only can affect energy production,but also change body's insulin sensitivity.Earlier research found that cold stress could cause some impairments of the central nervous system,heart and cerebral blood vessels,but recently we found that chronic cold exposure could decrease insulin resistance index and increase mitochondrial quantity,which prompted us to continue our exploration.Finally research results showed that epigenetic modifications and peroxisome proliferators-activated receptor-? coactivator-1?(PGC-1?)probably were involved in the processes.Epigenetic modifications are comprised of stable and heritable changes in gene function that occur without a change in DNA sequence,while PGC-1? is the key regulator of mitochondrial biogenesis.In a word,both of them are the new targets in preventing and treating metabolic disease.Objective: With mice mode,we tried to investigate how chronic cold exposure influence insulin sensitivity,mitochondrial quantity and energy metabolism related protein,discussing the regulation function of epigenetic modifications and PGC-1? in this process.Our study will offer us more knowledge to prevent and treat metabolic disease.Methods: Male mice(46 cases)at age of 8 weeks were used in the study,and the mice were divided into control group and cold exposure group in random.Cold exposure group was fed at temperature from-1? and 4 ? for 4 weeks to make animal model,but the control mice were fed at temperature from 20? and 25?.Above all,fasting blood glucose,blood insulin level and insulin resistance index were measured with enzymatic methods.Then,mitochondria of granular cells in cerebellar cortex in vivo were labeled with MitoTracker.Immunofluorescent labeling was carried out to visualized the insulin receptor substrate 2(IRS2),Obese receptor(Ob-R,a leptin receptor),voltage-dependent anion channel protein 1(VDAC1),cytochrome C(cytC),5-methylcytosine(5-mC),Histone deacetylase 1(HDAC1),DNA methylation related enzyme,mitochondrial fission and fusion proteins and peroxisome proliferators-activated receptor-? coactivator-1?(PGC-1?)positive cells in target area.Furthermore,the expressions of some proteins above were detected with Western blot.Results:(1)Chronic cold exposure could reduce the insulin resistance index(P < 0.01),with IRS2 positive cells and Ob-R positive cells increase in hippocampus as well(P < 0.01).(2)The expressions of mitochondrial energy-relative proteins,VDAC1 and cytC,were higher in cold group than in control group with both immunohistochemical staining and Western blot(P < 0.01).(3)Chronic cold exposure increased DNA hypermethylation and histone deacetylation in the pyramidal cells of CA1 area,and histone deacetylase 1(HDAC1)and DNA methylation relative enzymes were over expressed(P < 0.01).(4)Compared with control group,the number of mitochondria increased(P < 0.01)and the expression of mitochondrial fission,fusion protein and PGC-1? significantly increased(P < 0.01)in cold exposure group.Conclusion:(1)Chronic cold exposure can improve insulin resistance.DNA methylation,histone deacetylation and mitochondrial energy metabolism are involved in the processes.The epigenetic modifications are probably the basic mechanism of cold-induced insulin resistance decease.(2)Chronic cold exposure may enhance mitochondrial biosynthesis to increase the quantity of mitochondria by activating PGC-1?;while activated PGC-1? can induce the expression of mitochondrial morphology regulatory proteins under cold stress.The new balance of fission and fusion of mitochondria is established at cold environment,leading to adapt to cold situation. |
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