Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
FASEB J ; 28(12): 5398-405, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25172893

RESUMO

Low birth weight and rapid postnatal growth increases risk of cardiovascular-disease (CVD); however, underlying mechanisms are poorly understood. Previously, we demonstrated that rats exposed to a low-protein diet in utero that underwent postnatal catch-up growth (recuperated) have a programmed deficit in cardiac coenzyme Q (CoQ) that was associated with accelerated cardiac aging. It is unknown whether this deficit occurs in all tissues, including those that are clinically accessible. We investigated whether aortic and white blood cell (WBC) CoQ is programmed by suboptimal early nutrition and whether postweaning dietary supplementation with CoQ could prevent programmed accelerated aging. Recuperated male rats had reduced aortic CoQ [22 d (35±8.4%; P<0.05); 12 m (53±8.8%; P<0.05)], accelerated aortic telomere shortening (P<0.01), increased DNA damage (79±13% increase in nei-endonucleaseVIII-like-1), increased oxidative stress (458±67% increase in NAPDH-oxidase-4; P<0.001), and decreased mitochondrial complex II-III activity (P<0.05). Postweaning dietary supplementation with CoQ prevented these detrimental programming effects. Recuperated WBCs also had reduced CoQ (74±5.8%; P<0.05). Notably, WBC CoQ levels correlated with aortic telomere-length (P<0.0001) suggesting its potential as a diagnostic marker of vascular aging. We conclude that early intervention with CoQ in at-risk individuals may be a cost-effective and safe way of reducing the global burden of CVDs.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Suplementos Nutricionais , Ubiquinona/metabolismo , Animais , Doenças Cardiovasculares/enzimologia , Feminino , Estresse Oxidativo , Gravidez , Ratos Wistar , Telomerase/metabolismo , Ubiquinona/administração & dosagem
2.
Hepatology ; 50(6): 1796-808, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19816994

RESUMO

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) describes an increasingly prevalent spectrum of liver disorders associated with obesity and metabolic syndrome. It is uncertain why steatosis occurs in some individuals, whereas nonalcoholic steatohepatitis (NASH) occurs in others. We have generated a novel mouse model to test our hypothesis: that maternal fat intake contributes to the development of NAFLD in adult offspring. Female mice were fed either a high-fat (HF) or control chow (C) diet before and during gestation and lactation. Resulting offspring were fed either a C or a HF diet after weaning, to generate four offspring groups; HF/HF, HF/C, C/HF, C/C. At 15 weeks of age, liver histology was normal in both the C/C and HF/C offspring. Kleiner scoring showed that although the C/HF offspring developed nonalcoholic fatty liver, the HF/HF offspring developed NASH. At 30 weeks, histological analysis and Kleiner scoring showed that both the HF/C and C/HF groups had NAFLD, whereas the HF/HF had a more severe form of NASH. Therefore, exposure to a HF diet in utero and during lactation contributes toward NAFLD progression. We investigated the mechanisms by which this developmental priming is mediated. At 15 weeks of age, hepatic mitochondrial electron transport chain (ETC) enzyme complex activity (I, II/III, and IV) was reduced in both groups of offspring from HF-fed mothers (HF/C and HF/HF). In addition, measurement of hepatic gene expression indicated that lipogenesis, oxidative stress, and inflammatory pathways were up-regulated in the 15-week-old HF/C and HF/HF offspring. CONCLUSION: Maternal fat intake contributes toward the NAFLD progression in adult offspring, which is mediated through impaired hepatic mitochondrial metabolism and up-regulated hepatic lipogenesis.


Assuntos
Gorduras na Dieta/administração & dosagem , Fígado Gorduroso/etiologia , Lipogênese , Fenômenos Fisiológicos da Nutrição Materna , Mitocôndrias Hepáticas/metabolismo , Animais , Modelos Animais de Doenças , Transporte de Elétrons , Feminino , Regulação da Expressão Gênica , Receptores de Hialuronatos/genética , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Reação em Cadeia da Polimerase , Gravidez
3.
Am J Physiol Regul Integr Comp Physiol ; 297(3): R675-81, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19535678

RESUMO

We recently reported insulin resistance in adult offspring of obese C57BL/6J mice. We have now evaluated whether parameters of skeletal muscle structure and function may play a role in insulin resistance in this model of developmental programming. Obesity was induced in female mice by feeding a highly palatable sugar and fat-rich diet for 6 wk prior to pregnancy, and during pregnancy and lactation. Offspring of obese dams were weaned onto standard laboratory chow. At 3 mo of age, skeletal muscle insulin signaling protein expression, mitochondrial electron transport chain activity (ETC), muscle fiber type, fiber density, and fiber cross-sectional area were compared with that of offspring of control dams weaned onto the chow diet. Female offspring of obese dams demonstrated decreased skeletal muscle expression of p110beta, the catalytic subunit of PI3K (P < 0.01), as well as reduced Akt phosphorylation at Serine residue 473 compared with control offspring. Male offspring of obese dams demonstrated increased skeletal muscle Akt2 and PKCzeta expression (P < 0.01; P < 0.001, respectively). A decrease in mitochondrial-linked complex II-III was observed in male offspring of obese dams (P < 0.01), which was unrelated to CoQ deficiency. This was not observed in females. There were no differences in muscle fiber density between offspring of obese dams and control offspring in either sex. Sex-related alterations in key insulin-signaling proteins and in mitochondrial ETC may contribute to a state of insulin resistance in offspring of obese mice.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Resistência à Insulina , Insulina/metabolismo , Mitocôndrias Musculares/metabolismo , Obesidade/metabolismo , Músculo Quadríceps/metabolismo , Transdução de Sinais , Fenômenos Fisiológicos da Nutrição Animal , Animais , Peso Corporal , Classe I de Fosfatidilinositol 3-Quinases , Modelos Animais de Doenças , Feminino , Transportador de Glucose Tipo 4/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/enzimologia , Fibras Musculares Esqueléticas/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Músculo Quadríceps/enzimologia , Músculo Quadríceps/patologia , Receptor de Insulina/metabolismo , Fatores Sexuais , Ubiquinona/metabolismo
4.
Am J Clin Nutr ; 103(2): 579-88, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26718412

RESUMO

BACKGROUND: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. OBJECTIVES: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. DESIGN: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed "recuperated"). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase-polymerase chain reaction. RESULTS: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 µm) than in controls (5 ± 0.5 µm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 µg/mL per µg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). CONCLUSIONS: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Suplementos Nutricionais , Retardo do Crescimento Fetal/dietoterapia , Hepatite/prevenção & controle , Cirrose Hepática/prevenção & controle , Estresse Oxidativo , Ubiquinona/análogos & derivados , Animais , Citocinas/antagonistas & inibidores , Citocinas/sangue , Citocinas/metabolismo , Dieta com Restrição de Proteínas/efeitos adversos , Feminino , Desenvolvimento Fetal , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/imunologia , Retardo do Crescimento Fetal/fisiopatologia , Hepatite/etiologia , Hepatite/metabolismo , Hepatite/patologia , Hiperinsulinismo/etiologia , Hiperinsulinismo/prevenção & controle , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Desnutrição/fisiopatologia , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Complicações na Gravidez/fisiopatologia , Ratos Wistar , Organismos Livres de Patógenos Específicos , Ubiquinona/uso terapêutico , Desmame
5.
Endocrinology ; 156(10): 3528-37, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26214037

RESUMO

Low birth weight and rapid postnatal growth increases the risk of developing insulin resistance and type 2 diabetes in later life. However, underlying mechanisms and potential intervention strategies are poorly defined. Here we demonstrate that male Wistar rats exposed to a low-protein diet in utero that had a low birth weight but then underwent postnatal catch-up growth (recuperated offspring) had reductions in the insulin signaling proteins p110-ß (13% ± 6% of controls [P < .001]) and insulin receptor substrate-1 (39% ± 10% of controls [P < .05]) in adipose tissue. These changes were not accompanied by any change in expression of the corresponding mRNAs, suggesting posttranscriptional regulation. Recuperated animals displayed evidence of a proinflammatory phenotype of their adipose tissue with increased IL-6 (139% ± 8% [P < .05]) and IL1-ß (154% ± 16% [P < .05]) that may contribute to the insulin signaling protein dysregulation. Postweaning dietary supplementation of recuperated animals with coenzyme Q (CoQ10) (1 mg/kg of body weight per day) prevented the programmed reduction in insulin receptor substrate-1 and p110-ß and the programmed increased in IL-6. These findings suggest that postweaning CoQ10 supplementation has antiinflammatory properties and can prevent programmed changes in insulin-signaling protein expression. We conclude that CoQ10 supplementation represents an attractive intervention strategy to prevent the development of insulin resistance that results from suboptimal in utero nutrition.


Assuntos
Inflamação/metabolismo , Resistência à Insulina , Insulina/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Transdução de Sinais , Ubiquinona/análogos & derivados , Tecido Adiposo/metabolismo , Animais , Feminino , Perfilação da Expressão Gênica , Transtornos do Crescimento/fisiopatologia , Insulina/sangue , Lipídeos/sangue , Masculino , Exposição Materna , Camundongos , MicroRNAs/metabolismo , Estresse Oxidativo , Fenótipo , Ratos , Ratos Wistar , Ubiquinona/fisiologia
6.
Mol Metab ; 2(4): 480-90, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24327963

RESUMO

Studies in human and animals have demonstrated that nutritionally induced low birth-weight followed by rapid postnatal growth increases the risk of metabolic syndrome and cardiovascular disease. Although the mechanisms underlying such nutritional programming are not clearly defined, increased oxidative-stress leading to accelerated cellular aging has been proposed to play an important role. Using an established rodent model of low birth-weight and catch-up growth, we show here that post-weaning dietary supplementation with coenzyme Q10, a key component of the electron transport chain and a potent antioxidant rescued many of the detrimental effects of nutritional programming on cardiac aging. This included a reduction in nitrosative and oxidative-stress, telomere shortening, DNA damage, cellular senescence and apoptosis. These findings demonstrate the potential for postnatal antioxidant intervention to reverse deleterious phenotypes of developmental programming and therefore provide insight into a potential translatable therapy to prevent cardiovascular disease in at risk humans.

7.
Hypertension ; 51(2): 383-92, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18086952

RESUMO

Maternal obesity is increasingly prevalent and may affect the long-term health of the child. We investigated the effects of maternal diet-induced obesity in mice on offspring metabolic and cardiovascular function. Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a palatable obesogenic diet (16% fat, 33% sugar) for 6 weeks before mating and throughout pregnancy and lactation. Offspring of control (OC) and obese dams (OO) were weaned onto standard chow and studied at 3 and 6 months of age. OO were hyperphagic from 4 to 6 weeks of age compared with OC and at 3 months locomotor activity was reduced and adiposity increased (abdominal fat pad mass; P<0.01). OO were heavier than OC at 6 months (body weight, P<0.05). OO abdominal obesity was associated with adipocyte hypertrophy and altered mRNA expression of beta-adrenoceptor 2 and 3, 11 beta HSD-1, and PPAR-gamma 2. OO showed resistance artery endothelial dysfunction at 3 months, and were hypertensive, as assessed by radiotelemetry (nighttime systolic blood pressure at 6 months [mm Hg] mean+/-SEM, male OO, 134+/-1 versus OC, 124+/-2, n=8, P<0.05; female OO, 137+/-2 versus OC, 122+/-4, n=8, P<0.01). OO skeletal muscle mass (tibialis anterior) was significantly reduced (P<0.01) OO fasting insulin was raised at 3 months and by 6 months fasting plasma glucose was elevated. Exposure to the influences of maternal obesity in the developing mouse led to adult offspring adiposity and cardiovascular and metabolic dysfunction. Developmentally programmed hyperphagia, physical inactivity, and altered adipocyte metabolism may play a mechanistic role.


Assuntos
Adiposidade , Dieta , Hiperfagia/etiologia , Hipertensão/etiologia , Resistência à Insulina , Obesidade/etiologia , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Adipócitos/patologia , Adiposidade/genética , Animais , Artérias/fisiopatologia , Pressão Sanguínea , Capilares/patologia , Tamanho Celular , Feminino , Expressão Gênica , Teste de Tolerância a Glucose , Frequência Cardíaca , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/patologia , Obesidade/fisiopatologia , Pâncreas/metabolismo , Gravidez , Resistência Vascular
8.
Reprod Biomed Online ; 9(4): 418-24, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15511342

RESUMO

There is increasing evidence in humans that abnormal mitochondrial DNA (mtDNA) is associated with common degenerative disorders of the twenty-first century. MtDNA is exclusively female in origin and abnormalities in mtDNA can either be inherited, or generated de novo by adverse environmental factors that disturb mitochondrial DNA synthesis or destabilize mtDNA. The preimplantation period of development in mammals was thought to be relatively immune from environmentally induced changes to mtDNA, since no replication of mtDNA was thought to occur at this stage. This study demonstrates that there is a very short period of mtDNA synthesis immediately after fertilization, which can be affected by environmental stress. Adverse culture conditions during this phase of development could therefore alter the mitochondrial genome, with possible long-term consequences for the health of the offspring. The findings have relevance for all assisted reproduction programmes and for the rapidly emerging field of stem cell technologies.


Assuntos
DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Animais , Sequência de Bases , Blastocisto/metabolismo , Fase de Clivagem do Zigoto/metabolismo , Replicação do DNA , Feminino , Dosagem de Genes , Humanos , Camundongos , Gravidez , Técnicas de Cultura de Tecidos , Zigoto/metabolismo
9.
Semin Cell Dev Biol ; 15(5): 583-97, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15271304

RESUMO

The first developmental lineage allocation during the generation of the mouse blastocyst is to outer trophoblast or to inner pluriblast (inner cell mass; ICM) cells. This allocation seems to be initiated at the 8-cell stage, when blastomeres polarise. Polarisation is followed by differentiative divisions at the subsequent two cleavage divisions to generate polar outer and non-polar inner 16- and 32-cells. The key events in polarisation are regulated post-translationally through a cell contact-mediated pathway, which imposes a heritable determinant-like organisation on the blastomere cortex. Two proteins in particular, E-cadherin and ezrin, are intimately involved in the generation and stabilisation of developmentally significant information. Transcriptional differences between lineages appear to follow and may coincide with the lineage commitment of cells.


Assuntos
Padronização Corporal/fisiologia , Linhagem da Célula/fisiologia , Animais , Blastômeros/fisiologia , Caderinas , Proteínas do Citoesqueleto , Feminino , Camundongos , Óvulo/fisiologia , Fosfoproteínas/fisiologia , Trofoblastos/fisiologia
10.
Br J Nutr ; 88(5): 471-7, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12425727

RESUMO

Maternal malnutrition can lead to fetal abnormalities and increase susceptibility to disease in later life. Rat models have been developed to study the physiology and metabolism underlying this phenomenon. One particular model of 50 % protein restriction during pregnancy, the low-protein diet (LPD) supplemented with methionine, has been developed to investigate the underlying mechanisms. Recent studies have shown that rats fed a LPD during only the first 4 d of pregnancy produce offspring that develop hypertension. These results suggest that the very earliest stages of embryo development are susceptible to diet-induced heritable changes. We demonstrate a marked elevation of maternal serum homocysteine (hcy) concentrations during the initial phases of pregnancy in both rats and mice fed an LPD. Fetal growth and many of the circulating amino acids are similarly perturbed in both rats and mice fed the LPD during pregnancy, indicating that the response to the LPD diet is similar in rats and mice. These findings allow us to exploit the advantages of the mouse experimental system in future analyses aimed at understanding the molecular basis of fetal programming. Our present findings are discussed with particular reference to mechanisms which may initiate fetal programming, and to the feasibility of dietary interventions aimed at reducing early pregnancy loss and pre-eclampsia in man.


Assuntos
Blastocisto/metabolismo , Dieta com Restrição de Proteínas , Homocisteína/sangue , Modelos Animais , Fenômenos Fisiológicos da Nutrição Pré-Natal , Aborto Espontâneo/etiologia , Aminoácidos/sangue , Animais , Suscetibilidade a Doenças , Desenvolvimento Embrionário e Fetal , Feminino , Idade Gestacional , Metionina/administração & dosagem , Camundongos , Camundongos Endogâmicos , Pré-Eclâmpsia/etiologia , Gravidez , Ratos , Ratos Endogâmicos
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa