Mammary cell proliferation and catabolism of adipose tissues in nutrition-restricted lactating sows were associated with extracellular high glutamate levels
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摘要
Background: Persistent lactation,as the result of mammary cellular anabolism and secreting function,is dependent on substantial mobilization or catabolism of body reserves under nutritional deficiency.However,little is known about the biochemical mechanisms for nutrition-restricted lactating animals to simultaneously maintain the anabolism of mammary cells while catabolism of body reserves.In present study,lactating sows with restricted feed allowance(RFA)(n = 6),24% feed restriction compared with the control(CON) group(n = 6),were used as the nutrition-restricted model.Microdialysis and mammary venous cannulas methods were used to monitor postprandial dynamic changes of metabolites in adipose and mammary tissues.Results: At lactation d 28,the RFA group showed higher(P < 0.05) loss of body weight and backfat than the CON group.Compared with the CON group,the adipose tissue of the RFA group had higher(P < 0.05) extracellular glutamate and insulin levels,increased(P < 0.05) lipolysis related genes(HSL and ATGL) expression,and decreased(P < 0.05) glucose transport and metabolism related genes(VAMP8,PKLR and LDHB) expression.These results indicated that under nutritional restriction,reduced insulin-mediated glucose uptake and metabolism and increased lipolysis in adipose tissues was related to extracellular high glutamate concentration.As for mammary glands,compared with the CON group,the RFA group had up-regulated(P < 0.05) expression of Notch signaling ligand(DLL3) and receptors(NOTCH2 and NOTCH4),higher(P < 0.05) extracellular glutamate concentration,while expression of cell proliferation related genes and concentrations of most metabolites in mammary veins were not different(P > 0.05) between groups.Accordingly,piglet performance and milk yield did not differ(P > 0.05) between groups.It would appear that activation of Notch signaling and adequate supply of glutamate might assist mammogenesis.Conclusions: Mammary cell proliferation and catabolism of adipose tissues in nutrition-restricted lactating sows were associated with extracellular high glutamate levels.
Background: Persistent lactation,as the result of mammary cellular anabolism and secreting function,is dependent on substantial mobilization or catabolism of body reserves under nutritional deficiency.However,little is known about the biochemical mechanisms for nutrition-restricted lactating animals to simultaneously maintain the anabolism of mammary cells while catabolism of body reserves.In present study,lactating sows with restricted feed allowance(RFA)(n = 6),24% feed restriction compared with the control(CON) group(n = 6),were used as the nutrition-restricted model.Microdialysis and mammary venous cannulas methods were used to monitor postprandial dynamic changes of metabolites in adipose and mammary tissues.Results: At lactation d 28,the RFA group showed higher(P < 0.05) loss of body weight and backfat than the CON group.Compared with the CON group,the adipose tissue of the RFA group had higher(P < 0.05) extracellular glutamate and insulin levels,increased(P < 0.05) lipolysis related genes(HSL and ATGL) expression,and decreased(P < 0.05) glucose transport and metabolism related genes(VAMP8,PKLR and LDHB) expression.These results indicated that under nutritional restriction,reduced insulin-mediated glucose uptake and metabolism and increased lipolysis in adipose tissues was related to extracellular high glutamate concentration.As for mammary glands,compared with the CON group,the RFA group had up-regulated(P < 0.05) expression of Notch signaling ligand(DLL3) and receptors(NOTCH2 and NOTCH4),higher(P < 0.05) extracellular glutamate concentration,while expression of cell proliferation related genes and concentrations of most metabolites in mammary veins were not different(P > 0.05) between groups.Accordingly,piglet performance and milk yield did not differ(P > 0.05) between groups.It would appear that activation of Notch signaling and adequate supply of glutamate might assist mammogenesis.Conclusions: Mammary cell proliferation and catabolism of adipose tissues in nutrition-restricted lactating sows were associated with extracellular high glutamate levels.
Background: Persistent lactation,as the result of mammary cellular anabolism and secreting function,is dependent on substantial mobilization or catabolism of body reserves under nutritional deficiency.However,little is known about the biochemical mechanisms for nutrition-restricted lactating animals to simultaneously maintain the anabolism of mammary cells while catabolism of body reserves.In present study,lactating sows with restricted feed allowance(RFA)(n = 6),24% feed restriction compared with the control(CON) group(n = 6),were used as the nutrition-restricted model.Microdialysis and mammary venous cannulas methods were used to monitor postprandial dynamic changes of metabolites in adipose and mammary tissues.Results: At lactation d 28,the RFA group showed higher(P < 0.05) loss of body weight and backfat than the CON group.Compared with the CON group,the adipose tissue of the RFA group had higher(P < 0.05) extracellular glutamate and insulin levels,increased(P < 0.05) lipolysis related genes(HSL and ATGL) expression,and decreased(P < 0.05) glucose transport and metabolism related genes(VAMP8,PKLR and LDHB) expression.These results indicated that under nutritional restriction,reduced insulin-mediated glucose uptake and metabolism and increased lipolysis in adipose tissues was related to extracellular high glutamate concentration.As for mammary glands,compared with the CON group,the RFA group had up-regulated(P < 0.05) expression of Notch signaling ligand(DLL3) and receptors(NOTCH2 and NOTCH4),higher(P < 0.05) extracellular glutamate concentration,while expression of cell proliferation related genes and concentrations of most metabolites in mammary veins were not different(P > 0.05) between groups.Accordingly,piglet performance and milk yield did not differ(P > 0.05) between groups.It would appear that activation of Notch signaling and adequate supply of glutamate might assist mammogenesis.Conclusions: Mammary cell proliferation and catabolism of adipose tissues in nutrition-restricted lactating sows were associated with extracellular high glutamate levels.
引文
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2.Williams AM,Safranski TJ,Spiers DE,Eichen PA,Coate EA,Lucy MC.Effects of a controlled heat stress during late gestation,lactation,and after weaning on thermoregulation,metabolism,and reproduction of primiparous sows.J Anim Sci.2013;91:2700-14.
3.Oftedal OT.Use of maternal reserves as a lactation strategy in large mammals.P Nutr Soc.2000;59:99-106.
4.Girousse A,Tavernier G,Valle C,Moro C,Mejhert N,Dinel AL,et al.Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.PLoS Biol.2013;11:e1001485
5.Tucker HA.Quantitative estimates of mammary growth during various physiological states:a review.J Dairy Sci.1987;70(9):1958-66.
6.Kim SW,Hurley WL,Han IK,Easter RA.Changes in tissue composition associated with mammary gland growth during lactation in sows.J Anim Sci.1999;77(9):2510-6.
7.Capuco A,Ellis S,Hale S,Long E,Erdman R,Zhao X,et al.Lactation persistency:insights from mammary cell proliferation studies.J Anim Sci.2003;81:18-31.
8.Birsoy K,Wang T,Chen WW,Freinkman E,Abu-Remaileh M,Sabatini DM.An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis.Cell.2015;162:540-51.
9.Sullivan LB,Gui DY,Hosios AM,Bush LN,Freinkman E,Vander Heiden MG.Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells.Cell.2015;162:552-63.
10.Lunt SY,Vander Heiden MG.Aerobic glycolysis:meeting the metabolic requirements of cell proliferation.Annu Rev Cell Dev Bi.2011;27:441-64.
11.Chi C,Ronai D,Than MT,Walker CJ,Sewell AK,Han M.Nucleotide levels regulate germline proliferation through modulating GLP-1/notch signaling in C.elegans.Genes Dev.2016;30:307-20.
12.Callahan R,Egan SE.Notch signaling in mammary development and oncogenesis.J Mammary Gland Biol.2004;9:145-63.
13.Lane AN,Fan TW-M.Regulation of mammalian nucleotide metabolism and biosynthesis.Nucleic Acids Res.2015;43:2466-85.
14.Coloff JL,Murphy JP,Braun CR,Harris IS,Shelton LM,Kami K,et al.Differential glutamate metabolism in proliferating and quiescent mammary epithelial cells.Cell Metab.2016;23:867-80.
15.Nagao H,Nishizawa H,Bamba T,Nakayama Y,Isozumi N,Nagamori S,et al.Increased dynamics of tricarboxylic acid cycle and glutamate synthesis in obese adipose tissue:in vivo metabolic turnover analysis.J Biol Chem.2017;292:4469-83.
16.Ungerstedt J,Nowak G,Ungerstedt U,Ericzon BG.Microdialysis monitoring of porcine liver metabolism during warm ischemia with arterial and portal clamping.Liver Transplant.2009;15:280-6.
17.NRC.Nutrient requirements of swine.11th ed.Washionton DC:National Academies Press;2012.
18.Gessner DK,Grone B,Rosenbaum S,Most E,Hillen S,Becker S,et al.Effect of a negative energy balance induced by feed restriction in lactating sows on hepatic lipid metabolism,milk production and development of litters.Arch Anim Nutr.2015;69:399-410.
19.Sulabo RC,Jacela JY,Tokach MD,Dritz SS,Goodband RD,Derouchey JM,et al.Effects of lactation feed intake and creep feeding on sow and piglet performance.J Anim Sci.2010;88:3145-53.
20.Li H,Wan H,Mercier Y,Zhang X,Wu C,Wu X,et al.Changes in plasma amino acid profiles,growth performance and intestinal antioxidant capacity of piglets following increased consumption of methionine as its hydroxy analogue.Brit J Nutr.2014;112:855-67.
21.Zhong H,Li H,Liu G,Wan H,Mercier Y,Zhang X,et al.Increased maternal consumption of methionine as its hydroxyl analog promoted neonatal intestinal growth without compromising maternal energy homeostasis.JAnim Sci Biotechnol.2016;7:46.
22.Trottier NL,Shipley CF,Easter RA.A technique for the venous cannulation of the mammary gland in the lactating sow.J Anim Sci.1995;73:1390-5.
23.Hu CB,Solomon DD,Shields NL.Method for rendering a substrate surface antithrombogenic.EP.USA;1989.
24.Abrahamsson A,Dabrosin C.Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo Oncotarget.2015;6:22959-69.
25.Hansen AV,Strathe AB,Kebreab E,France J,Theil PK.Predicting milk yield and composition in lactating sows:a Bayesian approach.J Anim Sci.2012;90:2285-98.
26.Livak KJ,Schmittgen TD.Analysis of relative gene expression data using real-time quantitative pcr and the 2-ΔΔCTmethod.Methods.2001;25:402-8.
27.Nygard AB,Jorgensen CB,Cirera S,Fredholm M.Selection of reference genes for gene expression studies in pig tissues using SYBR green qPCR.BMC Mol Biol.2007;8:67.
28.Littell RC,Stroup WW,Milliken GA,Wolfinger RD,Schabenberger O.SAS for mixed models.2nd ed.Cary NC:SAS Institute Inc;2006.
29.Lassek WD,Gaulin SJ.Changes in body fat distribution in relation to parity in American women:a covert form of maternal depletion.Am J Phys Anthro.2006;131:295-302.
30.Kim SW,Jung HW,Kim CH,Kim KI,Chin HJ,Lee H.A new equation to estimate muscle mass from creatinine and cystatin c.PLoS One.2016;11:e0148495.
31.Zhao P,Yang L,Lopez JA,Fan J,Burchfield JG,Bai L,et al.Variations in the requirement for v-SNAREs in GLUT4 trafficking in adipocytes.J Cell Sci.2009122:3472-80.
32.Beg M,Abdullah N,Thowfeik FS,Altorki NK,McGraw TE.Distinct Akt phosphorylation states are required for insulin regulated Glut4 and Glut1-mediated glucose uptake.elife.2017;6:e26896.
33.Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation.Science.2009;324:1029-33.
34.Samuel VT,Shulman GI.Mechanisms for insulin resistance:common threads and missing links.Cell.2012;148:852-71.
35.Demine S,Tejerina S,Bihin B,Thiry M,Reddy N,Renard P,et al.Mild mitochondrial uncoupling induces HSL/ATGL-independent lipolysis relying on a form of autophagy in 3T3-L1 adipocytes.J Cell Physiol.2017;233:1247-65.
36.Frayn K,Khan K,Coppack S,Elia M.Amino acid metabolism in human subcutaneous adipose tissue in vivo.Clin Sci.1991;80:471-4.
37.Mitomo H,Watanabe Y,Matsuo Y,Niikura K,Ijiro K.Enzymatic synthesis of a DNA triblock copolymer that is composed of natural and unnatural nucleotides.Chem-Asian J.2015;10:455-60.
38.Millar ID,Calvert DT,Lomax MA,Shennan DB.The mechanism of L-glutamate transport by lactating rat mammary tissue.Biochim Biophys Acta.1996;1282:200-6.
39.Chi C,Han M.Notch signaling protects animals from nucleotide deficiency.Cell Cycle.2016;30:1941-2.
2.Williams AM,Safranski TJ,Spiers DE,Eichen PA,Coate EA,Lucy MC.Effects of a controlled heat stress during late gestation,lactation,and after weaning on thermoregulation,metabolism,and reproduction of primiparous sows.J Anim Sci.2013;91:2700-14.
3.Oftedal OT.Use of maternal reserves as a lactation strategy in large mammals.P Nutr Soc.2000;59:99-106.
4.Girousse A,Tavernier G,Valle C,Moro C,Mejhert N,Dinel AL,et al.Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.PLoS Biol.2013;11:e1001485
5.Tucker HA.Quantitative estimates of mammary growth during various physiological states:a review.J Dairy Sci.1987;70(9):1958-66.
6.Kim SW,Hurley WL,Han IK,Easter RA.Changes in tissue composition associated with mammary gland growth during lactation in sows.J Anim Sci.1999;77(9):2510-6.
7.Capuco A,Ellis S,Hale S,Long E,Erdman R,Zhao X,et al.Lactation persistency:insights from mammary cell proliferation studies.J Anim Sci.2003;81:18-31.
8.Birsoy K,Wang T,Chen WW,Freinkman E,Abu-Remaileh M,Sabatini DM.An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis.Cell.2015;162:540-51.
9.Sullivan LB,Gui DY,Hosios AM,Bush LN,Freinkman E,Vander Heiden MG.Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells.Cell.2015;162:552-63.
10.Lunt SY,Vander Heiden MG.Aerobic glycolysis:meeting the metabolic requirements of cell proliferation.Annu Rev Cell Dev Bi.2011;27:441-64.
11.Chi C,Ronai D,Than MT,Walker CJ,Sewell AK,Han M.Nucleotide levels regulate germline proliferation through modulating GLP-1/notch signaling in C.elegans.Genes Dev.2016;30:307-20.
12.Callahan R,Egan SE.Notch signaling in mammary development and oncogenesis.J Mammary Gland Biol.2004;9:145-63.
13.Lane AN,Fan TW-M.Regulation of mammalian nucleotide metabolism and biosynthesis.Nucleic Acids Res.2015;43:2466-85.
14.Coloff JL,Murphy JP,Braun CR,Harris IS,Shelton LM,Kami K,et al.Differential glutamate metabolism in proliferating and quiescent mammary epithelial cells.Cell Metab.2016;23:867-80.
15.Nagao H,Nishizawa H,Bamba T,Nakayama Y,Isozumi N,Nagamori S,et al.Increased dynamics of tricarboxylic acid cycle and glutamate synthesis in obese adipose tissue:in vivo metabolic turnover analysis.J Biol Chem.2017;292:4469-83.
16.Ungerstedt J,Nowak G,Ungerstedt U,Ericzon BG.Microdialysis monitoring of porcine liver metabolism during warm ischemia with arterial and portal clamping.Liver Transplant.2009;15:280-6.
17.NRC.Nutrient requirements of swine.11th ed.Washionton DC:National Academies Press;2012.
18.Gessner DK,Grone B,Rosenbaum S,Most E,Hillen S,Becker S,et al.Effect of a negative energy balance induced by feed restriction in lactating sows on hepatic lipid metabolism,milk production and development of litters.Arch Anim Nutr.2015;69:399-410.
19.Sulabo RC,Jacela JY,Tokach MD,Dritz SS,Goodband RD,Derouchey JM,et al.Effects of lactation feed intake and creep feeding on sow and piglet performance.J Anim Sci.2010;88:3145-53.
20.Li H,Wan H,Mercier Y,Zhang X,Wu C,Wu X,et al.Changes in plasma amino acid profiles,growth performance and intestinal antioxidant capacity of piglets following increased consumption of methionine as its hydroxy analogue.Brit J Nutr.2014;112:855-67.
21.Zhong H,Li H,Liu G,Wan H,Mercier Y,Zhang X,et al.Increased maternal consumption of methionine as its hydroxyl analog promoted neonatal intestinal growth without compromising maternal energy homeostasis.JAnim Sci Biotechnol.2016;7:46.
22.Trottier NL,Shipley CF,Easter RA.A technique for the venous cannulation of the mammary gland in the lactating sow.J Anim Sci.1995;73:1390-5.
23.Hu CB,Solomon DD,Shields NL.Method for rendering a substrate surface antithrombogenic.EP.USA;1989.
24.Abrahamsson A,Dabrosin C.Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo Oncotarget.2015;6:22959-69.
25.Hansen AV,Strathe AB,Kebreab E,France J,Theil PK.Predicting milk yield and composition in lactating sows:a Bayesian approach.J Anim Sci.2012;90:2285-98.
26.Livak KJ,Schmittgen TD.Analysis of relative gene expression data using real-time quantitative pcr and the 2-ΔΔCTmethod.Methods.2001;25:402-8.
27.Nygard AB,Jorgensen CB,Cirera S,Fredholm M.Selection of reference genes for gene expression studies in pig tissues using SYBR green qPCR.BMC Mol Biol.2007;8:67.
28.Littell RC,Stroup WW,Milliken GA,Wolfinger RD,Schabenberger O.SAS for mixed models.2nd ed.Cary NC:SAS Institute Inc;2006.
29.Lassek WD,Gaulin SJ.Changes in body fat distribution in relation to parity in American women:a covert form of maternal depletion.Am J Phys Anthro.2006;131:295-302.
30.Kim SW,Jung HW,Kim CH,Kim KI,Chin HJ,Lee H.A new equation to estimate muscle mass from creatinine and cystatin c.PLoS One.2016;11:e0148495.
31.Zhao P,Yang L,Lopez JA,Fan J,Burchfield JG,Bai L,et al.Variations in the requirement for v-SNAREs in GLUT4 trafficking in adipocytes.J Cell Sci.2009122:3472-80.
32.Beg M,Abdullah N,Thowfeik FS,Altorki NK,McGraw TE.Distinct Akt phosphorylation states are required for insulin regulated Glut4 and Glut1-mediated glucose uptake.elife.2017;6:e26896.
33.Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation.Science.2009;324:1029-33.
34.Samuel VT,Shulman GI.Mechanisms for insulin resistance:common threads and missing links.Cell.2012;148:852-71.
35.Demine S,Tejerina S,Bihin B,Thiry M,Reddy N,Renard P,et al.Mild mitochondrial uncoupling induces HSL/ATGL-independent lipolysis relying on a form of autophagy in 3T3-L1 adipocytes.J Cell Physiol.2017;233:1247-65.
36.Frayn K,Khan K,Coppack S,Elia M.Amino acid metabolism in human subcutaneous adipose tissue in vivo.Clin Sci.1991;80:471-4.
37.Mitomo H,Watanabe Y,Matsuo Y,Niikura K,Ijiro K.Enzymatic synthesis of a DNA triblock copolymer that is composed of natural and unnatural nucleotides.Chem-Asian J.2015;10:455-60.
38.Millar ID,Calvert DT,Lomax MA,Shennan DB.The mechanism of L-glutamate transport by lactating rat mammary tissue.Biochim Biophys Acta.1996;1282:200-6.
39.Chi C,Han M.Notch signaling protects animals from nucleotide deficiency.Cell Cycle.2016;30:1941-2.