| Intrauterine growth retardation(IUGR)refers to the fetal growth and development lag in the uterus due to genetic or environmental factors.The natural incidence of IUGR in pig production is as high as 15 to 20%,which could result in high perinatal mortality,compromised growth performance,feed efficiency and body composition,bringing a huge economic loss to animal husbandry production.Studies have shown that dyslipidemia or ectopic fat deposition play an important role in the negative effects of IUGR.Mitochondria are the main sites of fatty acids oxidation,which can be used as substrates to produce adenosine triphosphate(ATP)and heat through oxidative phosphorylation.In addition,reactive oxygen species are inevitably produced in mitochondria as a byproduct in the process of oxidative metabolism.Antioxidant capacity is essential for mitochondrial function.Mitochondria are abundant in liver and skeletal muscle,which are the most active tissues for fatty acid oxidation.Resveratrol,a natural polyphenol,has been demonstrated to improve mitochondrial biogenesis,fatty acids oxidation and redox status.In view of this,this study used IUGR and normal birth weight(NBW)pigs as the reseaech objects to investigate the effects of IUGR and resveratrol on the fat metabolism at different growth stages,to analysis the role of mitochondria in the effects of IUGR and resveratrol from levels of organs and molecules,to analysis the key role of antioxidant capacity in mitochondrial function,to explore the potential nutritional strategies for the improvement of fat metabolism and mitochondrial functions in IUGR pigs,in order to improve the quality of livestock products and health status in IUGR pigs.1 Effects of IUGR and resveratrol on the growth performance and fat metabolism in pigsThis experiment was conducted to inverstigate the effects of IUGR and resveratrol on the growth performance,organs index,meat quality,plasma biochemical parameters,adipose tissues morphology,and fat metabolism in the liver and longissimus dorsi muscle of pigs at different growth stages.Thirty six NBW neonatal pigltes and 36 IUGR littermates were selected from 36 healthy sows with the same parity and similar expected day of farrowing based on birth weight,and were fed with 80 mg resveratrol/kg body weight/d or the same volume of 0.5%carboxymethylcellulose at 7 to 21 days of age.Then the offspring were fed with a basal diet containing 300 mg/kg resveratrol or a basal diet from weaning to 150 days of age.Therefore,the experiment was divided into 4 groups(6 replicates per group,3 pigs per replicate):NC group(NBW+vehicle),NR group(NBW+resveratrol),IC group(IUGR+vehicle)and IR group(IUGR+resveratrol).At 21,49 and 150 days of age,plasma,adipose tissues(perirenal and dorsal fat),liver and longissimus dorsi muscle samples were collected for subsequent analysis.The results showed that:(1)compared with NBW,IUGR decreased average daily gain(ADG,22.98%)at 7 to 21 days of age(P<0.05),and ADG(31.54%and 22.55%)and average daily feed intake(ADFI,32.72%and 22.93%)at 22 to 49and 50 to 90 days of age(P<0.05).Resveratrol decreased(P<0.05)ADG(11.06%,10.92%and 10.89%)and ADFI(13.6%,12.33%and 11.09%)at 22 to 49,50 to 90 and 91 to 150 days of age.Resveratrol decreased ADFI in NBW weaned piglets at 22 to 49 days of age(P<0.05),but had no significant effect on ADFI in IUGR weaned piglets at this stage(P>0.05).(2)Compared with NBW,IUGR decreased(P<0.05)the absolute weight of heart(26.71%),liver(18.44%)and kidney(23.91%),and increased(P<0.05)the relative weight of liver(12.94%),spleen(41.21%),and pancreas(29.41%)in the sucking piglets;IUGR decreased(P<0.05)the absolute weight of heart(35.70%),liver(29.14%),spleen(30.52%),kidney(32.71%)and pancreas(41.52%)in the weaned piglets,increased the relative weight of liver(9.68%)and perirenal fat(38.65%)in the weaned piglets,and also decreased(P<0.05)the absolute weight of liver(13.28%),spleen(17.51%)and kidney(15.88%)in the finishing pigs.Resveratrol increased(P<0.05)the absolute weight of heart(18.28%)and kidney(14.72%),but decreased(P<0.05)the relative weight of pancreas(15.38%)in the sucking piglets.Resveratrol increased(P<0.05)the absolute weight of kidney(11.73%)in the weaned piglets,but decreased(P<0.05)the absolute weight of liver(10.62%)in the finishing pigs.Resveratrol alleviated the IUGR-caused decreased absolute weight of heart,liver,spleen,kidney and pancreas,and reduced relative weight of liver in the weaned piglets(P<0.05).(3)Compared with NBW,the finishing pigs exposed to IUGR had higher luminance in the longissimus dorsi muscle(P<0.05).Administration of RSV decreased drip loss at 24 h in the longissimus dorsi muscle of the finishing pigs(P<0.05).Resveratrol had a tendency to decrease yellowness in the longissimus dorsi muscle of IUGR finishing pigs(P=0.084).(4)Compared with NBW,in the plasma of IUGR pigs,the level of free fatty acid(FFA,31.43%)during the sucking period and the concentrations of low density lipoprotein cholesterol(LDL-C)during the weaned(25.74%)and finishing(19.77%)period were decreased(P<0.05),and the content of urea nitrogen(UN,26.97%)during the sucking period were increased(P<0.05).Resveratrol decreased FFA(44.33%)and glucose(Glu,18.83%)concentrations during the weaned period,creatinine(Cre,18.98%)and FFA(17.27%)levels during the finishing period and the contents of Cre(20.00%),UN(21.52%),triglycerides(TG,26.48%)and FFA(40.84%)during the sucking period in the plasma of pigs(P<0.05),and increased the level of high density lipoprotein cholesterol(25.97%)in the plasma of the weaned piglets(P<0.05).Resveratrol inhibited the increased Cre level during the sucking period and elevated FFA content during the finishing period in the plasma of IUGR pigs(P<0.05),and decreased the plasma Glu level in IUGR weaned piglets(P<0.05).Compared with NBW,in the plasma of IUGR pigs,insulin like growth factor 1(IGF1,63.33%)content at 21 days of age and insulin(Ins,40.95%)level and homeostasis model assessment of insulin resistance(HOMA-IR,45.74%)at 49 days of age were decreased(P<0.05),and HOMA-IR(65.92%),Ins(66.27%)and IGF1(35.43%)concentrations at 150 days of age were increased(P<0.05).Resveratrol alleviated the increased plasma Ins content and enhanced HOMA-IR in IUGR finishing pigs(P<0.05).(5)Compared with NBW,IUGR decreased(P<0.05)the average dorsal fat adipocyte size in the suckling piglets and increased(P<0.05)the average perirenal adipocyte size in the finishing pigs.Resveratrol increased the average perirenal and dorsal adipocytes size in the suckling piglets(P<0.05),and decreased the average perirenal and dorsal adipocytes size in the finishing pigs(P<0.05).(6)Compared with NBW,the lipid levels in the liver and longissimus dorsi muscle of IUGR pigs were in abnormal state for a long time,and carnitine palmitoyltransferase 1α(CPT1α)gene expression was permanently downregulated,which plays an important role in fat metabolism disorder of IUGR pigs.However,the expression of peroxisome proliferator activated receptorα(PPARα),sterol regulatory element binding protein 1c and its downstream genes related to lipid synthesis existed in time and tissue specificity.Resveratrol could regulate the genes and proteins expression related to fat metabolism in the liver and longissimus dorsi muscle of pigs at different growth stages to some extent,especially PPARαprotein level or the gene expression of CPT1αwere continuously upregulated,which improves the fat metabolism homeostasis and prevents lipid ectopic deposition induced by IUGR.2 Effects of IUGR and resveratrol on the mitochondrial functions in the liver of pigsThe aim of this study was to investigate the effects of IUGR and resveratrol on the mitochondrial biogenesis and oxidative phosphorylation in the liver of pigs at different growth stages.The design of the experiment was the same as that of trial 1.The results showed that:(1)the IUGR-induced the alteration of hepatic mitochondrial DNA(mt DNA)copy number,the concentrations of ATP,oxidized form of nicotinamide adenine dinucleotide(NAD~+)and reduced form of nicotinamide adenine dinucleotide(NADH)were alleviated by resveratrol in different degrees(P<0.05).Compared with NBW,in the liver,the mitochondrial complex IV(64.76%)activity in the sucking period,complex I(49.33%),II(49.43%)and IV(70.05%)activities in the weaned period,and complex III(38.37%)activity in the finishing period were all decreased by IUGR(P<0.05).Resveratrol enhanced the hepatic mitochondrial complex II(217.99%)and III(78.38%)activities in the finishing pigs(P<0.05).Resveratrol alleviated the inhibited mitochondrial complex I activity during the sucking period and complex III activity during the weaned period in the liver of IUGR piglets(P<0.05).(2)In the liver of IUGR pigs,the level of adenosine 5’-monophosphate-activated protein kinaseα(AMPKα)phosphorylation during the sucking period,the expression of nuclear respiratory factor l(NRF1),estrogen-related receptorα(ERRα),and polymeraseγ(POLG)genes during the weaned period,and sirtuin l(SIRT1)and peroxisome proliferation activated receptorγcoactivator-1α(PGC1α)proteins,NRF1,ERRα,and POLG genes expression during the finishing period were all decreased(P<0.05).Resveratrol increased the transcription level of NRF1 gene in the liver of IUGR suckling piglets(P<0.05).Resveratrol upregulated the proteins expression of SIRT1 and PGC1αduring the weaned period and the genes expression of NRF1,ERRα,mitochondrial transcription factor A(TFAM)and POLG during the finishing period in the liver of pigs(P<0.05).(3)IUGR negatively affected the hepatic genes expression related to mitochondrial oxidative phosphorylation in pigs at different growth stages after birth,involving mitochondrial complex I-V,especially at 49days of age;resveratrol could upregulate the genes expression related to mitochondrial oxidative phosphorylation in the liver of pigs at different growth stages in varying degrees,and improve the negative effect of IUGR on the genes expression related to oxidative phosphorylation in the liver,but the regulation effect is best in the finishing period.3 Effects of IUGR and resveratrol on the antioxidant capacity in the liver and its mitochondria of pigsThe aim of this study was to investigate the effects of IUGR and resveratrol on the antioxidant capacity in the liver and its mitochondria of pigs at different growth stages.The design of the experiment was the same as that of trial 1.The results showed that:(1)compared with NBW,IUGR permanently increased the hepatic protein carboxyls(PC)and malondialdehyde(MDA)levels(P<0.05),permanently inhibited its mitochondrial glutathione peroxidase(GPX)activity(P<0.05),decreased its mitochondrial glutathione reductase(GR)activity during the weaned and finishing period(P<0.05),increased the hepatic mitochondrial MDA level in piglets(P<0.05),and decreased the hepatic glutathione(GSH)level in the sucking piglets(P<0.05).Resveratrol enhanced(P<0.05)the hepatic GSH level(28.33%)and GR(37.24%)activity,and its mitochondrial Mn superoxide dismutase(Mn-SOD)activity(41.61%)during the sucking period and the hepatic total superoxide dismutase(T-SOD,9.03%)and GPX(17.33%)activities during the weaned period,decreased(P<0.05)the hepatic mitochondrial MDA levels during the sucking(27.48%)and finishing(27.70%)period,and increased(P<0.05)the hepatic mitochondrial GSH level(135.21%)in the finishing pigs.Resveratrol continuously improved the hepatic increased MDA concentration in IUGR pigs(P<0.05),and alleviated the decreased hepatic GR activity and mitochondrial GPX activity in IUGR finishing pigs(P<0.05).Resveratrol alleviated(P<0.05)the increased PC level in the hepatic mitochondria during the sucking period and the elevated MDA content in the hepatic mitochondria during the weaned period caused by IUGR.(2)Compared with NBW,in the liver of IUGR pigs,the gene expression of superoxide dismutase1(SOD1,43.02%)at 21 days of age,the genes expression of heme oxygenase 1(HO1,52.68%),glutamate-cysteine ligase modifier subunit(GCLM,46.28%),GPX1(47.35%),GPX4(41.28%)and GR(40.00%)at 49 days of age,and the genes expression of nuclear factor erythroid-derived 2-like 2(Nrf2,38.86%),kelch-like ech-associated protein 1(Keap1,33.63%),glutamate-cysteine ligase catalytic subunit(GCLC,46.26%),and GR(33.04%)at150 days of age were all downregulated(P<0.05).Resveratrol upregulated the hepatic m RNA transcription of GPX1 gene(36.87%)in the sucking piglets,GCLC gene(104.37%)in the weaned piglets and HO1(47.85%),GCLM(56.41%),GPX4(40.61%)and GR(42.86%)genes in the finishing pigs(P<0.05).Compared with NBW,IUGR decreased Nrf2 protein expression in the liver of the finishing pigs(P<0.05).Resveratrol decreased the expression of Keap1 protein in the liver of IUGR finishing pigs(P<0.05).4 Effects of IUGR and resveratrol on the mitochondrial functions in the longissimus dorsi muscle of pigsThis study was conducted to investigate the effects of IUGR and resveratrol on the mitochondrial biogenesis and oxidative phosphorylation in the longissimus dorsi muscle of pigs at different growth stages.The design of the experiment was the same as that of trial 1.The results showed that:(1)compared with NBW,IUGR decreased(P<0.05)the activities of mitochondrial complex IV(46.94%)at the weaned stage and complexes I(42.61%),II(69.83%),III(52.08%)and V(41.15%)activities at the fattening stage.Resveratrol increased the activities of mitochondrial complex V(418.34%)at the sucking stage and complexes II(224.68%)and V(98.51%)at the fattening stage(P<0.05).Resveratrol alleviated the decreased mitochondrial complex I activity in the longissimus dorsi muscle of IUGR finishing pigs(P<0.05).(2)Compared with NBW,IUGR permanently inhibited(P<0.05)the expression of AMPKαphosphorylation,PGC1αprotein and its downstream mitochondrial biogenesis transcription factors m RNA.Thus,mt DNA copy number were downregulated for a long time by IUGR(P<0.05).In addition,IUGR inhibited the expression of SIRT1 protein in the longissimus dorsi muscle of the sucking and weaned piglets(P<0.05).On the contrary,in the longissimus dorsi muscle,resveratrol increased(P<0.05)SIRT1 or PGC1αexpression of pigltes and the m RNA expression of POLG in the sucking piglets,enhanced the longissimus dorsi muscular mt DNA copy number in piglets,alleviated(P<0.05)the inhibitory effect of IUGR on the longissimus dorsi muscular mt DNA copy number of piglets.(3)The long-term negative effects of IUGR on ATP,NAD~+and NADH concentrations in the longissimus dorsi muscle could be improved by resveratrol(P<0.05).In addition,IUGR had a permanent negative effect on the genes expression related to mitochondrial oxidative phosphorylation in the longissimus dorsi muscle,which was most obvious in the fattening period,especially the expression of mitochondrial complex II coding gene succinate dehydrogenase complex flavoprotein subunit A were continuously downregulated.5 Effects of IUGR and resveratrol on the antioxidant capacity in the longissimus dorsi muscle and its mitochondria of pigsThis study was conducted to investigate the effects of IUGR and resveratrol on the antioxidant capacity in the longissimus dorsi muscle and its mitochondria of pigs at different growth stages.The design of the experiment was the same as that of trial 1.The results showed that:(1)compared with NBW,the longissimus dorsi muscle and its mitochondria in IUGR exhited persistently oxidative stress.At 21 days of age,the longissimus dorsi muscular and its mitochondrial PC and MDA contents were increased(P<0.05),and the longissimus dorsi muscular mitochondrial GR activities were decreased(P<0.05)in IUGR piglets.At 49days of age,the longissimus dorsi muscular and its mitochondrial MDA contents were increased(P<0.05),and the longissimus dorsi muscular T-SOD activity were decreased(P<0.05).At 150 days of age,the longissimus dorsi muscular and its mitochondrial MDA contents were increased(P<0.05),and the mitochondrial GPX and GR activities were decreased(P<0.05).Resveratrol inhibited T-SOD activity(14.47%)in the longissimus dorsi muscle of the weaned piglets(P<0.05),decreased the longissimus dorsi muscular mitochondrial MDA contents(23.50%)and Mn-SOD activity(33.59%)and increased its GR activity(98.99%)in the finishing pigs(P<0.05).Resveratrol alleviated the IUGR-induced increased MDA contents and decreased GPX activity in the longissimus dorsi muscle of the sucking and finishing pigs(P<0.05).Resveratrol inhibited(P<0.05)the elevated MDA contents in the longissimus dorsi muscular mitochondria of IUGR sucking piglets,and decreased GR activity in the longissimus dorsi muscular mitochondria of IUGR weaned piglets.(2)Compared with NBW,the expression of GCLM(29.59%)and GPX4(32.24%)genes in the sucking period,HO1(51.10%)and GCLM(41.73%)genes in the weaned period,GCLM(30.77%)and GPX4(40.44%)genes in the finishing period were downregulated in the longissimus dorsi muscle of IUGR(P<0.05).In the longissimus dorsi muscle,Nrf2(47.44%),GCLC(70.63%)and GPX1(57.79%)genes expression of the suckling piglets,HO1(64.71%)and GCLM(49.11%)genes expression of the weaned piglets and GCLM gene expression(40.44%)of the finishing pigs were upregulated by resveratrol(P<0.05).Resveratrol decreased the gene expression of GR in the longissimus dorsi muscle of IUGR sucking piglets(P<0.05),and alleviated the IUGR-induced downregulated GR gene expression in the longissimus dorsi muscle of the weaned piglets(P<0.05).Compared with NBW,IUGR decreased(P<0.05)Nrf2 proteins expression at 21 and 49 days of age and increased(P<0.05)Keap1 protenin level at 150 days of age in the longissimus dorsi muscle of pigs.Resveratrol upregulated the longissimus dorsi muscular Nrf2 protein expression in the sucking piglets(P<0.05).The conclusion are as follows:(1)The inhibitory effects of IUGR on postnatal growth of piglets decreased with age,and IUGR increased the luminance in the longissimus dorsi muscule of the finishing pigs.IUGR could induce persistent lipid metabolism disorders in pigs after birth,one of the most important reasons is its long-term inhibition of mitochondrial fatty acid?-oxidation in the liver and longissimus dorsi muscle.(2)The long-term disturbance of AMPK/PGC1αpathway is an important reason for the continuous impaired mitochondrial biosynthesis and oxidative phosphorylation in the longissimus dorsi muscle of IUGR pigs;the long-term inhibition of hepatic mitochondrial biogenesis and oxidative phosphorylation in IUGR pigs were also observed;the persistent downregulated oxidative phosphorylation in the longissimus dorsi muscle by IUGR is most obvious in the finishing period,and the most obvious effects of IUGR on hepatic oxidative phosphorylation is during the weaned period.The liver,longissimus dorsi muscle and its mitochondria of IUGR pigs showed persistent oxidative stress.(3)Resveratrol inhibited the growth performance of pigs at different growth stages except during lactation.However,resveratrol had no effect on the growth performance of IUGR pigs.Resveratrol can reduce the drip loss in the longissimus dorsi muscule of the finishing pigs,and had a tendency to improve the yellowness in the longissimus dorsi muscle of IUGR finishing pigs.Resveratrol can improve the fat metabolism of pigs at different growth stages after birth,prevent the IUGR-induced lipid ectopic deposition,one of the important mechanisms is the continuous enhancement of mitochondrial fatty acid?-oxidation utilization in the liver and longissimus dorsi muscle.(4)Resveratrol could improve the mitochondrial function and antioxidant capacity in the liver and longissimus dorsi muscle of pigs at different growth stages,and alleviate the persistent weakening of mitochondrial function and antioxidant capacity in the liver and longissimus dorsi muscle caused by IUGR,but the mechanism was tissue and time dependent.Resveratrol had the best effect on the mitochondrial oxidative phosphorylation in the liver during the fattening period.Resveratrol had a better effect on the mitochondrial biosynthesis in the longissimus dorsi muscle of piglets in the early postnatal period. |
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