The mechanistic target of rapamycin complex 1 pathway involved in hepatic gluconeogenesis through peroxisome-proliferator-activated receptorγcoactivator-1a

Cattle can efficiently perform de novo generation of glucose through hepatic gluconeogenesis to meet post-weaning glucose demand.Substantial evidence points to cattle and non-ruminant animals being characterized by phylogenetic features in terms of their differing capacity for hepatic gluconeogenesis,a process that is highly efficient in cattle yet the underlying mechanism remains unclear.Here we used a variety of transcriptome data,as well as tissue and cell-based methods to uncover the mechanisms of high-efficiency hepatic gluconeogenesis in cattle.We showed that cattle can efficiently convert propionate into pyruvate,at least partly,via high expression of acyl-CoA synthetase short-chain family member 1(ACSS1),propionyl-CoA carboxylase alpha chain(PCCA),methylmalonyl-CoA epimerase(MCEE),methylmalonyl-CoA mutase(MMUT),and succinate-CoA ligase(SUCLG2)genes in the liver(P<0.01).Moreover,higher expression of the rate-limiting enzymes of gluconeogenesis,such as phosphoenolpyruvate carboxykinase(PCK)and fructose 1,6-bisphosphatase(FBP),ensures the efficient operation of hepatic gluconeogenesis in cattle(P<0.01).Mechanistically,we found that cattle liver exhibits highly active mechanistic target of rapamycin complex 1(mTORC1),and the expressions of PCCA,MMUT,SUCLG2,PCK,and FBP genes are regulated by the activation of mTORC1(P<0.001).Finally,our results showed that mTORC1 promotes hepatic gluconeogenesis in a peroxisome proliferator-activated receptor γ coactivator 1a(PGC-1a)dependent manner.Collectively,our results not only revealed an important mechanism responsible for the quantitative differences in the efficiency of hepatic gluconeogenesis in cattle versus non-ruminant animals,but also established that mTORC1 is indeed involved in the regulation of hepatic gluconeogenesis through PGC-1a.These results provide a novel potential insight into promoting hepatic gluconeogenesis through activated mTORC1 in both ruminants and mammals.

Effectiveness of sub-maximal intermittent exercise on muscle glycogen depletion, PGC-1<i>α</i>and PDK-4 gene expression

Several metabolic gene expressions are regulated in concert with muscle glycogen status. We hypothesized that intermittent exercise performed at high but sub-maximal intensities with long recovery periods would induce a low glycogen state that would stimul- ate peroxisome proliferator-activated receptor-γ coa- ctivator-1α (PGC1-α) and pyruvate dehydrogenase kinase-4 (PDK-4) gene expression in muscle. Nine young human subjects performed two intermittent exercise sessions. One session consisted of 60 s cycling bouts at VO2max (IE100%), and the other session consisted of 75 s cycling bouts at 80% VO2max (IE80%). Twelve bouts of exercise were completed in both sessions with a 4 min rest between each bout. Muscle specimens were obtained at pre-exercise and immediately, 1.5 h and 3 h post-exercise. Muscle gly- cogen was significantly decreased after both sessions (IE100%, 94.1 ± 5.8 to 38.7 ± 5.5 mmol/kg w.w.;IE80%, 94.6 ± 9.1 to 53.3 ± 4.8 mmol/kg w.w.;both P α and PDK- 4 mRNA expression were significantly increased after exercise in both IE100% and IE80% (PGC-1α: ~3.7 and ~2.9-fold, respectively;PDK-4: ~11.1 and ~3.5-fold, respectively;all P 100% than in IE80% (P a and PDK-4 mRNA expression, suggesting that increasing exercise intensity contributes to muscle glycogen depletion and PDK-4 mRNA expression in human skeletal muscle.

Danqi Tablet(丹七片)Regulates Energy Metabolism in Ischemic Heart Rat Model through AMPK/SIRT1-PGC-1α Pathway

Objective To investigate the cardioprotective effect of Danqi Tablet(DQT,丹七片)on ischemic heart model rats and the regulative effect on energy metabolism through peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α).Methods Rat ischemic heart model was induced by ligation of left anterior descending coronary artery.Totally 40 Sprague-Dawley rats were randomly divided into sham group,model group,DQT group(1.5 mg/kg daily)and trimetazidine(TMZ)group(6.3 mg/kg daily)according to a random number table,10 rats in each group.Twenty-eight days after continuous administration,cardiac function was assessed by echocardiography and the structures of myocardial cells were observed by hematoxylin-eosin staining.The level of adenosine triphosphate(ATP)in myocardial cells was measured by ATP assay kit.Expressions level of key transcriptional regulators,including PGC-1α,Sirtuin 1(SIRT1),AMP-activated protein kinase(AMPK),and downstream targets of PGC-1α,such as mitofusin 1(MFN1),mitofusin 2(MFN2)and superoxide dismutase 2(SOD2)were measured by Western blot.Expression level of PGC-1αwas examined by immunohistochemical staining.Results The rat ischemic heart model was successfully induced and the heart function in model group was compromised.Compared with the model group,DQT exerted cardioprotective effects,up-regulated the ATP production in myocardial cells and inhibited the infiltration of inflammatory cells in the margin area of infarction of the myocardial tissues(P<0.01).The expressions of PGC-1α,SIRT1 and AMPK were increased in the DQT group(all P<0.05).Furthermore,the downstream targets,including MFN1,MFN2 and SOD2 were up-regulated(P<0.05 or P<0.01).Compared with the TMZ group,the expression levels of PGC-1α,MFN1 and SOD2 were increased by DQT treatment(P<0.05 or P<0.01).Conclusion DQT regulated energy metabolism in rats with ischemic heart model through AMPK/SIRT1-PGC-1αpathway.PGC-1αmight serve as a promising target in the treatment of ischemic heart disease.

Sirtuins Function as the Modulators in Aging-related Diseases in Common or Respectively

INTRODUCTIONAccording to the demographics, the world population over 60 years will double from 605 million to 2 billion people between 2000 and 2050. Aging is a complex process in which the organism and its ability to respond to external stresses become progressive decline.