A dieta hiperlipídica (high-fat, HF) materna durante a gestação e/ou lactação aumenta a susceptibilidade da prole para o desenvolvimento de doenças crônicas na fase adulta. Verificar a hipótese que a ingestão materna de dieta HF nos períodos críticos de desenvolvimento (gestação e/ou lactação) predispõe à doença não alcoólica do fígado gorduroso e alterações pancreáticas e no tecido adiposo de camundongos machos adultos. Camundongos C57BL/6 fêmeas receberam durante a gestação e/ou lactação dieta padrão (standard chow, SC) ou HF. Filhotes machos foram divididos em cinco grupos: SC provenientes de mães SC; G provenientes de mães HF durante a gestação; L provenientes de mães HF durante a lactação; GL/HF provenientes de mães HF durante a gestação/lactação, mantendo a mesma dieta HF no período pós-natal (do desmame aos 3 meses deidade); GL provenientes de mães HF durante a gestação/lactação trocando a dieta para SC no período pós-natal (do desmame aos 3 meses deidade). Foi analisada ao longo do experimento a massa corporal da prole. No sacrifício (3 meses), o fígado, o pâncreas e a gordura epididimária foram removidos, pesados e processados e o sangue foi coletado para análise bioquímica. Ao nascimento e ao desmame, filhotes GL/HF foram mais pesados (+6% e +44%, p<0,05, respectivamente) que os filhotes SC. Os filhotes G apresentaram resistência à insulina e menor expressão do transportador de glicose no fígado (GLUT-2). A esteatose hepática foi observada nos grupos G, L, GL e principalmente nos filhotes do grupo GL/HF. A expressão hepática da proteína ligante de elementos regulatórios de esteróis (SREBP-1c) estava aumentada nos filhotes G, GL e GL/HF. Os filhotes G, GL e GL/HF apresentaram hipertrofia da ilhota pancreática e dos adipócitos quando comparados com o grupo SC. O consumo de dieta HF durante a gestação mostra-se ser o período mais prejudicial para os filhotes adultos de camundongos. A programação metabólica por dieta HF leva ao remodelamento adverso do fígado, do pâncreas e do tecido adiposo / Maternal high-fat diet (HF) during gestation and/or lactation period increases the susceptibility to development of chronic disease in offspring adult life. This work aimed to verify the hypothesis that maternal intake of high-fat diet in critical periods of pregnancy and/or suckling period predisposes to non alcoholic fatty liver disease, pancreatic and adipose tissue alterations in adulthood mice offspring. C57BL/6 female mice were fed, during gestation and/or lactation phases, with standard chow (SC) or HF diet. Male pups were divided into 5 groups: SC- from SC fed dam; G- from HF fed dam during gestation period; L- from HF fed dam during lactation period; GL- from HF fed dam during gestation and lactation periods and GL/HF- from HF fed dam during gestation and lactation, maintaining HF diet from post-weaning to adulthood. We analyzed body mass in all experiment, and at the euthanasia (3 mo-old), liver, pancreas and adipose tissue were removed, weighted and embedded. Blood was collected to biochemical analyses. At birth and at weaning, GL/HF pups were heavier than SC pups (+6% and +44%, p<0.05, respectively). G offspring showed insulin resistance and lower glucose transporter-2 expression (GLUT-2). Hepatic steatosis was present in G, L, GL and mainly in GL/HF offspring. Sterol regulatory element-binding protein-1c (SREBP-1c) expression was higher in G, GL and GL/HF offspring. It is important to mention that pancreatic islet hypertrophy and adipocyte hypertrophy were affected in G, GL and GL/HF offspring in comparison to SC. HF diet administration during gestation period is worse than lactation period. Furthermore, this type of programming by HF predisposes to adverse remodeling in liver, pancreas and adipose tissue in adult mice offspring

No description available.

A dieta hiperlipídica (high-fat, HF) materna durante a gestação e/ou lactação aumenta a susceptibilidade da prole para o desenvolvimento de doenças crônicas na fase adulta. Verificar a hipótese que a ingestão materna de dieta HF nos períodos críticos de desenvolvimento (gestação e/ou lactação) predispõe à doença não alcoólica do fígado gorduroso e alterações pancreáticas e no tecido adiposo de camundongos machos adultos. Camundongos C57BL/6 fêmeas receberam durante a gestação e/ou lactação dieta padrão (standard chow, SC) ou HF. Filhotes machos foram divididos em cinco grupos: SC provenientes de mães SC; G provenientes de mães HF durante a gestação; L provenientes de mães HF durante a lactação; GL/HF provenientes de mães HF durante a gestação/lactação, mantendo a mesma dieta HF no período pós-natal (do desmame aos 3 meses deidade); GL provenientes de mães HF durante a gestação/lactação trocando a dieta para SC no período pós-natal (do desmame aos 3 meses deidade). Foi analisada ao longo do experimento a massa corporal da prole. No sacrifício (3 meses), o fígado, o pâncreas e a gordura epididimária foram removidos, pesados e processados e o sangue foi coletado para análise bioquímica. Ao nascimento e ao desmame, filhotes GL/HF foram mais pesados (+6% e +44%, p<0,05, respectivamente) que os filhotes SC. Os filhotes G apresentaram resistência à insulina e menor expressão do transportador de glicose no fígado (GLUT-2). A esteatose hepática foi observada nos grupos G, L, GL e principalmente nos filhotes do grupo GL/HF. A expressão hepática da proteína ligante de elementos regulatórios de esteróis (SREBP-1c) estava aumentada nos filhotes G, GL e GL/HF. Os filhotes G, GL e GL/HF apresentaram hipertrofia da ilhota pancreática e dos adipócitos quando comparados com o grupo SC. O consumo de dieta HF durante a gestação mostra-se ser o período mais prejudicial para os filhotes adultos de camundongos. A programação metabólica por dieta HF leva ao remodelamento adverso do fígado, do pâncreas e do tecido adiposo / Maternal high-fat diet (HF) during gestation and/or lactation period increases the susceptibility to development of chronic disease in offspring adult life. This work aimed to verify the hypothesis that maternal intake of high-fat diet in critical periods of pregnancy and/or suckling period predisposes to non alcoholic fatty liver disease, pancreatic and adipose tissue alterations in adulthood mice offspring. C57BL/6 female mice were fed, during gestation and/or lactation phases, with standard chow (SC) or HF diet. Male pups were divided into 5 groups: SC- from SC fed dam; G- from HF fed dam during gestation period; L- from HF fed dam during lactation period; GL- from HF fed dam during gestation and lactation periods and GL/HF- from HF fed dam during gestation and lactation, maintaining HF diet from post-weaning to adulthood. We analyzed body mass in all experiment, and at the euthanasia (3 mo-old), liver, pancreas and adipose tissue were removed, weighted and embedded. Blood was collected to biochemical analyses. At birth and at weaning, GL/HF pups were heavier than SC pups (+6% and +44%, p<0.05, respectively). G offspring showed insulin resistance and lower glucose transporter-2 expression (GLUT-2). Hepatic steatosis was present in G, L, GL and mainly in GL/HF offspring. Sterol regulatory element-binding protein-1c (SREBP-1c) expression was higher in G, GL and GL/HF offspring. It is important to mention that pancreatic islet hypertrophy and adipocyte hypertrophy were affected in G, GL and GL/HF offspring in comparison to SC. HF diet administration during gestation period is worse than lactation period. Furthermore, this type of programming by HF predisposes to adverse remodeling in liver, pancreas and adipose tissue in adult mice offspring

Gestational hypothyroidism is considerably prevalent. Low maternal thyroid hormones (THs) levels during pregnancy may affect several physiological systems in the offspring. Similarly, an inadequate maternal nutrition during pregnancy is implicated as the origin of many metabolic and cardiovascular diseases in the offspring. Therefore, gestational hypothyroidism, in addition to an inadequate maternal nutrition could trigger an even worse profile in the neuroendocrine, metabolic and feeding behavior throughout postnatal life of the offspring. The aim of this study was to assess metabolic aspects and ingestive behavior of the offspring of rats treated with high fat diet (HD) during gestation associated with experimental gestational hypothyroidism (EGH). On gestational day (GD) 3, we started to feed pregnant rats with the HD, and on GD 9, we started to induce EGH with 0.02% methimazole in drinking water, ad libitum. HD and EGH were only interrupted on the day of birth. The pregnant rats were weighted and monitored for the amount of food and water ingested from GD 3 up to GD 20. In the offspring, body development indexes were measured from postnatal day (PND) 1 up to PND 120. At PND 60, we performed the insulin tolerance test (ITT), glucose tolerance test (GTT), biochemical measurements, in both genders. Furthermore, food, water and 0.3 M NaCl ingestive behaviors were measured in male offspring at PND 30, 60, 90 and 120. Data were analyzed by two- or three-way ANOVAs with Bonferroni posttest. Male offspring from hypothyroid rats submitted to HD (OHT + HD) showed higher hematocrit, triglycerides, cholesterol and urea sera levels when compared to male offspring from hypothyroid rats submitted to control diet (OHT + CD). Moreover, female OHT + HD had higher glucose sensitivity at 30 minutes on the GTT when compared to OHT + CD (p<0.05) and also to offspring from euthyroid rats (OET) + HD (p<0.01). However, we observed no differences in fasting glycemia and ITT in female offspring from different groups. In conclusion, the association of EGH and HD during gestation caused a significant deficit in body development and dyslipidemia in male offspring, whereas female offspring exhibit higher glucose sensitivity. Thus, this data show, for the first time, how the association between low maternal THs with HD predict an abnormal metabolic profile in offspring, and give us an insert about the origin of several unknown metabolic diseases. / O hipotireoidismo gestacional apresenta considerável prevalência e já está devidamente documentado que a carência de hormônios tireoideanos durante a gestação gera repercussão na maturação dos sistemas fisiológicos de controle durante a vida pós-natal. Da mesma forma, inúmeras evidências apontam que o aporte nutricional inadequado durante a vida intrauterina, dependente do hábito alimentar materno, afeta o funcionamento orgânico na vida pós-natal. Assim, acredita-se que quantidade insuficiente dos hormônios tireoideanos durante a vida intrauterina associado ao estado nutricional inadequado das mães durante a gestação pode predispor, de modo particular, ao surgimento de diversas desordens neuroendócrinas, metabólicas e comportamentais ao longo da vida pós-natal. O objetivo do presente estudo foi avaliar os aspectos metabólicos e o comportamento ingestivo da prole de ratas induzidas ao hipotireoidismo associado à dieta hiperlipídica durante a gestação. A partir do 3º dia de gestação (DG) as ratas prenhas receberam dieta hiperlipídica e, a partir do 9º DG, iniciou-se, também, a indução do hipotireoidismo gestacional experimental (HGE) adicionando metimazol 0,02% na água de beber. Tanto a dieta quanto a indução ao hipotireoidismo foram interrompidos no dia do parto. Nas ratas prenhas foi realizado o acompanhamento da massa corporal e da ingestão alimentar do 3º DG ao 20º DG. Na prole foram avaliados a massa corporal e o comprimento da cauda, semanalmente, do 1º dia pós-natal (DPN) aos 120º DPN e, aos 60 PDN, realizaram-se o teste de tolerância à insulina (TTI), o teste de tolerância à glicose (TTG), dosagens bioquímicas e o peso relativo dos órgãos, em ambos os sexos. Além disso, foram investigados o comportamento ingestivo de ração, água e NaCl 0,3 M somente nos machos da prole aos 30, 60, 90 e 120 DPN. Os dados foram submetidos à ANOVA de duas ou três vias, e em seguida ao pós-teste de Bonferroni. Os machos da prole de ratas submetidas à associação do hipotireoidismo com a dieta hiperlipídica (PRH + DH) maior hematócrito e maiores concentrações de triglicérides, colesterol e ureia quando comparados aos machos da prole de ratas hipotireoideanas com dieta controle (PRH + DC). As fêmeas da PRH + DH apresentaram maior sensibilidade à glicose, aos 30 minutos, no teste de tolerância à glicose, quando comparadas as fêmeas da PRH + DC (p<0,05) e as fêmeas da prole de ratas eutireoideanas com dieta hiperlipídica (PRE + DH) (p<0,01), entretanto não foram encontradas diferenças, nas fêmeas dos grupos estudados, na glicemia de jejum e no teste de tolerância à insulina. O HGE associado à dieta hiperlipídica, exclusivamente durante a gestação, está associado a déficit no desenvolvimento corporal e dislipidemia na vida pós-natal dos machos dessa prole, enquanto as fêmeas apresentam maior sensibilidade à glicose. Assim, esses dados mostram, pela primeira vez, que a associação do HGE com a dieta hiperlipídica promove alteração no perfil metabólico da prole e demonstra que alterações no ambiente intrauterino pode ser a causa de diversas doenças metabólicas que, atualmente, não apresentam uma causa definida.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The consumption of foods high in sodium and saturated fat but low in fiber in other essential nutrients is known as Western Diet and is directly associated with metabolic and autonomic changes and the emergence of cardiovascular disease. In addition, studies have shown that eating disorders such as lack or excess food in early life promotes structural and functional adaptations in the fetus culminating in the emergence of diseases in adulthood. The resistance training (RT) has been used as a non pharmacological therapy in the treatment of various diseases, including, cardiovascular, however, the effect of RT on the cardiovascular control mechanisms have not been fully explored. The present study investigated the effects of low intensity TR autonomic modulation and the biochemical profile of rats exposed to a Western diet during the perinatal period. Wistar rats received control diet or Western during pregnancy and lactation. The rats were divided into three groups: control (C), sedentary Western Diet (WS) and Western diet + TR (WTR). After 60 days, the animals began the protocol with TR 5 times a week for 4 weeks. After the animals were surgery to evaluate pulse interval variability and blood pressure, and baroreflex sensitivity (BRS). Blood samples were collected for biochemical analysis. The RT reduced mean arterial pressure (WTR= 108.2±3.7 vs WS= 121±2.5 mmHg, p <0.05), systolic arterial pressure (WTR= 135.2±3.1 vs WS= 151.5±3.4 mmHg, p <0.05), diastolic blood pressure (WTR= 89.1±2.8 vs 99.4±2.3 WS= mmHg, p <0.05). An increase in the BRS (WTR= 1.9±0.23 vs WS= 1.1±0.14 ms/mmHg, p <0.05). Furthermore, it was observed that the RT was able to reduce vascular sympathetic modulation when compared to the WS group (WTR= 5.48±1.033 vs WS= 8.25±1.018 mmHg2, p <0.05). Biochemical parameters, found difference in blood glucose (WTR= 116.2±4.6 vs WS= 153.8±6.3 mg/dL, p <0.05), total cholesterol (TC) (WTR= 67.0±3.8 vs WS= 85.6±3.4 mg/dL, p <0.05) and high (HDL) lipoproteins (WTR= 57.2±3.5 vs WS= 41.8±2.8 mg/dL, p <0.05) and low density lipoprotein (LDL) (WTR= 14.2±2.2 vs WS= 31.0±3.2 mg/dL, p <0.05). These results suggest that low-intensity TR promotes adaptations beneficial to the cardiovascular system, mediated by adjustments in the autonomic control mechanisms and improved biochemical profile of these animals. / O consumo de alimentos ricos em sódio e gordura saturada, mas pobre em fibras em outros nutrientes essenciais é conhecido como Dieta Ocidental e está diretamente associado a alterações metabólicas, autonômicas e o surgimento de doenças cardiovasculares. Além disso, estudos tem mostrado que distúrbios alimentares como a falta ou excesso de nutrientes no início da vida promove adaptações estruturais e funcionais no feto culminando no surgimento de doenças na fase adulta. O treinamento resistido (TR) vem sendo utilizado como terapia não farmacológica no tratamento de diversas doenças, dentre elas, as cardiovasculares, porém, o efeito do TR sobre os mecanismos de controle cardiovascular nao foram completamente explorados. O presente estudo investigou os efeitos do TR de baixa intensidade na modulação autonômica e no perfil bioquímico de ratos expostos a uma dieta ocidental durante o período perinatal. Ratas Wistar receberam dieta controle ou ocidental durante a gravidez e lactação. Os filhotes foram divididos em três grupos: Controle (C), Dieta ocidental sedentário (OCS) e dieta ocidental + TR (OCTR). Aos 60 dias de vida, os animais iniciaram o protocolo de TR realizado 5 vezes por semana durante 4 semanas. Ao fim, os animais foram cirurgiados para posterior registro da variabilidade do intervalo de pulso e da pressão arterial, bem como a sensibilidade do barorreflexo (SBR). Amostras de sangue foram coletadas para análise bioquímica. O TR reduziu a pressão arterial média (OCTR= 108,2±3,7 vs OCS= 121±2,5 mmHg, p<0,05), pressão arterial sistólica (OCTR= 135,2±3,1 vs OCS= 151,5±3,4 mmHg, p<0,05) e pressão arterial diastólica (OCTR= 89,1±2,8 vs OCS= 99,4±2,3 mmHg, p<0,05). Houve aumento na SBR (OCTR= 1,9±0,23 vs OCS= 1,1±0,14 ms/mmHg, p<0,05). Além disso, observou-se que o TR foi capaz de reduzir a modulação simpática vascular quando comparado ao grupo OCS (OCTR= 5,48±1,033 vs OCS= 8,25±1,018 mmHg2, p<0,05). Nos parâmetros bioquímicos, foi observada diferença na glicemia (OCTR= 116,2±4,6 vs OCS= 153,8±6,3 mg/dL, p<0,05), colesterol total (CT) (OCTR= 67,0±3,8 vs OCS= 85,6±3,4 mg/dL, p<0,05) e lipoproteínas de alta (HDL) (OCTR= 57,2±3,5 vs OCS= 41,8±2,8 mg/dL, p<0,05) e baixa densidade (LDL) (OCTR= 14,2±2,2 vs OCS= 31,0±3,2 mg/dL, p<0,05). Estes resultados sugerem que o TR de baixa intensidade promove adaptações benéficas ao sistema cardiovascular, mediadas por ajustes nos mecanismos de controle autonômico e melhora no perfil bioquímico destes animais.

La santé maternelle et la santé pédiatrique font partie des priorités de santé publique mondiale. La présente thèse a pour objectif d’élargir les connaissances portant sur l’influence de la santé maternelle durant la grossesse sur la santé pondérale et cardiométabolique de la population pédiatrique. Une première étude a montré qu’une exposition intra-utérine à une ou plusieurs conditions gestationnelles sous-optimales (diabète gestationnel, désordres hypertensifs de la grossesse, tabagisme maternel durant la grossesse) avait un effet délétère sur la santé pondérale et cardiométabolique de la population pédiatrique et que cet effet était spécifique au sexe. Une seconde étude a montré que l’efficacité mécanique et l’oxydation des substrats énergétiques (lipides et glucides) au repos et durant l’exercice ne sont pas altérées dans cette population en comparaison avec les enfants non exposés. Ainsi, ce résultat suggère que d’autres mécanismes seraient à l’origine des effets délétères des conditions gestationnelles sous-optimales sur la santé pondérale et cardiométabolique de cette population. Enfin, la troisième étude a montré que seule l’activité physique d’intensité légère réduisait l’effet délétère d’une exposition intra-utérine à plus d’une condition gestationnelle sous-optimale sur le taux de cholestérol à lipoprotéine de haute densité chez les garçons. De plus, une durée de sommeil correspondant aux recommandations canadiennes actuelles n’avait pas d’effet protecteur vis-à-vis du risque d’obésité abdominale (enfants) et d’obésité (filles) dans le contexte d’une exposition au tabagisme maternel durant la grossesse. Par ailleurs, les autres saines habitudes de vie telles que l’activité physique d’intensité moyenne à élevée et une alimentation riche en fruits et légumes, en produits laitiers et en produits céréaliers n’ont pas contrecarré les effets délétères d’une exposition intra-utérine à une ou plusieurs conditions gestationnelles sous-optimales sur la santé pondérale et cardiométabolique des enfants. L’ensemble de ces résultats souligne l’importance de la santé maternelle durant la grossesse pour la santé pondérale et cardiométabolique de la population pédiatrique. Par ailleurs, étant donné que ces effets délétères ne sont que peu contrecarrés par les habitudes de vie durant l’enfance, il reste important de continuer les efforts de prévention et de prise en charge des conditions gestationnelles sous-optimales auprès des femmes enceintes qui les présentent. En terminant, il est important de continuer à explorer les mécanismes sous-jacents à ces effets délétères et à déterminer si des interventions en habitudes de vie peuvent prévenir l’obésité et les facteurs de risque cardiométaboliques dans cette population. / Maternal and children’s health are major worldwide public health concerns. The current thesis aimed to explore the impact of maternal health during pregnancy on children’s and adolescents’ health and included three original research projects. The first study found that a prenatal exposure to independent or combined suboptimal gestational factors (SGF : gestational diabetes mellitus, hypertensive disorders during pregnancy, maternal smoking during pregnancy) was positively associated with obesity and cardiometabolic risk factors in children around puberty, and these associations were sex-dependent. The second study found that children exposed to one SGF display a similar physiological response in terms of mechanical efficiency and substrate oxidation at rest and during exercise (submaximal and maximal) in comparison with non-exposed children. The third study of the thesis found that light-intensity physical activity reduced the adverse impact of prenatal exposure to combined SGF on high density lipoprotein-cholestrol levels in boys. A sleep duration within the range of the current Canadian recommendations for sleep did not mitigate the risk of high waist circumference (children) and obesity (girls) in a context of exposure to maternal smoking during pregnancy. Furthermore, other lifestyle factors such as moderate-to-vigorous physical activity and a healthy diet (intakes of: fruits and vegetables, grains, and dairy products), did not mitigate the adverse impact of a prenatal exposure to independent or combined SGF on children’s risk of obesity and cardiomeatbolic outcomes. Taken together, these results suggest that it is important to continue maternal SGF prevention and management programs to provide optimal health for children. Moreover, future studies should also develop and evaluate the impact of lifestyle habits interventions to design future prevention strategies during childhood and adolescence to reduce obesity and cardiometabolic risk factors in this population.

<p>NB: I had another committee member, Dr. Mark Larché; and would like to have his name included in the document.</p> <p>Thank you.</p> / <p><strong>Introduction: </strong>Increasing incidence of chronic immune diseases are mirrored by changing disease risk factors, which include maternal stress during pregnancy. To date, no studies have investigated the impact of prenatal stress challenge (PNS) on the fetal immune system. Fetal liver and bone marrow represent major sources of hematopoietic stem cells (HSC) at mid gestation, which differentiate and mature in the thymus. Disturbance of immune development may cause immune impairment in later life. Further, progesterone is recognized as a critical part of feto-maternal interaction. This study aimed to determine if PNS interferes with normal fetal immune development in mice and the impact of progesterone supplementation on stress effects. <strong>Methods: </strong>DBA/2J-mated BALB/c dams were sorted into three groups: control, PNS (gestation days (GDs) 12.5 and 14.5) and PNS plus progesterone supplementation (DHD). Fetal tissue was collected on GDs 16.5 and 18.5. Flow cytometric analysis examined frequency and phenotype of fetal immune cell populations: HSC in fetal liver and bone marrow, and different stages of T cell maturation and regulatory T (Treg) cells in the thymus. Fetal tails were collected to determine fetal sex by PCR analysis. <strong>Results: </strong>PNS induced a decrease in organ size on GD16.5, which was not seen on GD18.5 and was reversed by DHD treatment. PNS altered the percentage and absolute number of HSC within the liver and bone marrow populations, on GD16.5 and 18.5. There was a significant lag in T cell maturation as demonstrated by the altered expression of CD3 and skewed CD3-:CD3+ ratio. There was a significant decrease in Treg cells within CD3+ thymic cells in response to PNS. PNS effects in the thymus were ameliorated by DHD treatment. There was no PNS-induced sex bias. <strong>Conclusions: </strong>These results indicate that PNS compromises the developing fetal immune system, which could account for impaired immune responses in adults with chronic immune disease, and provide evidence for a therapeutic role of progesterone supplementation.</p> / Master of Science (MSc)

Sabe-se que algumas alterações nutricionais maternas durante o período perinatal estão associadas com doenças metabólicas na vida adulta das proles, tais como diabetes melito tipo 2, resistência à insulina, obesidade e hipertensão arterial. O período da gestação em que estas alterações nutricionais influenciam a prole na idade adulta ainda não está elucidado. Modificações epigenéticas têm sido propostas como mecanismos responsáveis por estas desordens metabólicas. Ratas Wistar de doze semanas de idade foram alimentadas com dieta com conteúdo baixo (HO - 0,15% NaCl) ou normal (NR - 1,3% NaCl) de sódio desde o primeiro dia de gestação até o nascimento da prole ou HO durante a primeira (HO10) ou segunda (HO20) metade da gestação. O peso corpóreo e a ingestão de água e ração foram avaliados semanalmente durante a gestação. Teste de tolerância à insulina (ITT) e à glicose (GTT) e HOMA-IR foram realizados nas proles adultas. Expressão gênica por qRT-PCR e metilação do DNA na região promotora dos genes foram mapeadas utilizando tratamento com bissulfito de sódio e avaliadas por pirosequenciamento. O ganho de peso materno foi menor no HO e HO20 na terceira semana de gestação em comparação com NR e HO10. O peso ao nascimento da prole foi menor em machos e fêmeas dos grupos HO e HO20 em relação ao NR e HO10. O HOMA-IR foi maior nos machos com 12 semanas de idade do grupo HO em comparação com NR e com 20 semanas de idade do grupo HO10 em comparação com NR e HO20. Nas fêmeas com 12 semanas de idade o HOMA-IR foi maior no HO10 comparado com HO. Os níveis de insulina no soro foram maiores tanto nos machos com 20 semanas de idade do grupo HO10 comparado com NR quanto nas fêmeas com 12 semanas de idade do grupo HO10 comparado com HO. A área sob a curva do GTT indicou intolerância à glicose nos machos do grupo HO. A porcentagem de metilação das ilhas CpG no promotor dos genes de Igf1, Igf1r, Ins1, Ins2 e Insr no fígado de machos e fêmeas neonatais e no fígado, tecido adiposo branco e músculo em machos com 20 semanas de idade foi influenciada pela baixa ingestão de sal durante a gestação. Nenhuma destas alterações foi identificada nas fêmeas com 20 semanas de idade. Em conclusão, a baixa ingestão de sal na segunda metade da gestação é responsável pelo baixo peso ao nascimento em ambos os sexos. A intolerância à glicose observada na prole adulta ocorreu somente se a dieta hipossódica é dada durante a gestação inteira. Por outro lado, a resistência à insulina em resposta ao consumo de dieta hipossódica durante a gestação está relacionada com o momento em que ocorre este insulto e com o envelhecimento da prole. Também foi observado que alterações na metilação do promotor do gene Igf1 está correlacionado com o baixo peso ao nascimento em resposta a ingestão de dieta hipossódica durante a gestação / It is known that some maternal nutritional alterations during pregnancy are associated with metabolic disorders in adult offspring, such as insulin resistance, type 2 diabetes mellitus, obesity and arterial hypertension. The period of pregnancy in which these nutritional alterations influence adult offspring remains uncertain. Epigenetic changes are proposed to underlie these metabolic disorders. Twelve-week-old female Wistar rats were fed a low-salt (LS - 0.15% NaCl) or normal-salt (NS - 1.3% NaCl) diet since the first day of gestation until delivery or LS during the first (LS10) or second (LS20) half of gestation. Body weight, food and water intake were weekly evaluated during gestation. Blood glucose, insulin (ITT) and glucose (GTT) tolerance tests, HOMA-IR were performed in adult offspring. Gene expression and DNA methylation were mapped using bisulfite treatment evaluated by pyrosequencing in the male and female neonates and adult offspring. Weight gain was lower in LS and LS20 dams than in NS and LS10 dams in the third week of pregnancy. Birth weights were lower in male and female LS20 and LS rats compared with NS and LS10 neonates. HOMA-IR was higher in 12-week-old LS males compared with NS and in 20-week-old male LS10 rats compared with NS and LS20 rats. In 12-week-old LS10 females, HOMA-IR was higher than in LS. Serum insulin levels were higher in 20 week-old LS10 male compared with NS rats and in 12-week-old LS10 female compared to LS rats. The area under the curve of GTT indicated glucose intolerance in 12- and 20-week-old LS male. Methylation of CpG islands of the Insr, Igf1, Igf1r, Ins1 and Ins2 genes in liver in neonates male and female offspring and liver, white adipose tissue and muscle in 20-week-old male offspring were influenced by low-salt intake during pregnancy. None of these alterations was identified in 20-week-old females. In conclusion, low-salt diet consumption in the second half of pregnancy can result in low birth weights in the males and females offspring. Glucose intolerance observed in adult offspring occurred only if low salt intake was given throughout pregnancy. However, insulin resistance in response to low salt intake during pregnancy is related to the time at which this insult occurs and to the age of the offspring. Alterations in the DNA methylation of Igf1 were observed to be correlated with low birth weight in response to low salt feeding during pregnancy

A greater understanding of critical periods of body weight regulation, including pregnancy, may aid in efforts to optimize weight management strategies for the mother and her baby. The gestational period has been implicated to play, in the child, a vital role in the developmental origins of obesity and other cardiometabolic diseases later in life. Therefore, we initially examined existing literature on the role of maternal obesity and its link to pediatric obesity and documented the known underlying physiological mechanisms responsible for this relationship while suggesting potential intervention targets that may improve maternal-fetal outcomes. In a second paper, we aimed to quantify maternal predictors of large for gestational age (LGA) neonates in the Ottawa and Kingston (OaK) birth cohort with specific hypotheses verifying the independent contribution of maternal prepregnancy body mass index (BMI) and excessive gestational weight gain (GWG) to fetal overgrowth. This paper also highlights the clinical utility of the revised 2009 Institute of Medicine GWG guidelines and discusses the potential role of physiological factors underlying the observed associations between BMI, excessive GWG and LGA neonates. As a follow-up to our population-level analysis (i.e., OAK cohort), papers three and four highlight how the insulin-like growth factor (IGF) axis, a vital regulator of growth and development, may be compromised at the molecular level in cases of maternal obesity (paper 3) and excessive GWG (paper 4). In paper 3 we show that maternal obesity is associated with attenuated expression of IGF binding protein-4 (IGFBP4) in umbilical cord blood and discuss how this may preferentially promote fetal adipogenesis. The effects of excessive GWG on IGF axis protein expression are addressed in paper four where we show that excessive weight gain during pregnancy is associated with increased expression of IGFBP3 in maternal circulation in normoglycemic term pregnancies. In this paper we discuss the potential inhibitory role of IGFBP3 on adipogenesis and how it relates to glucose intolerance during pregnancy. Recognizing that both obesity and excessive GWG can alter physiological processes in mother and her baby, appropriate evidence-based interventions are warranted to best optimize outcomes. In paper five, we discuss the results of a study which sought to assess patient information channels and knowledge of nutrition and physical activity during pregnancy with the intent that these findings be applied to best design efficacious strategies that cater to the needs of our target group of pregnant women. In our analysis we show that the majority of pregnant women studied would be willing to participate in a lifestyle intervention for their own personal health and that of their child. Of great interest was the observation that most women were not informed of the importance of pregnancy-specific energy intake, or made aware of their own healthy GWG targets. Additionally, many of the respondents reported receiving no information pertaining to appropriate physical activity recommendations; despite the fact that the vast majority of participants consider this lifestyle modality to be safe during their pregnancy. Finally in paper six, we build on the results of our previous work and evaluate the risks and benefits of physical activity during pregnancy on maternal-fetal outcomes through a review of the literature and note that engaging in non-sedentary pursuits during gestation may aid in maternal weight regulation, protect against metabolic disorders and optimize neonatal birth weight and body composition. Overall, the collective nature of the papers presented in this dissertation provides qualitative and quantitative evidence to support not only the complexity of body weight regulation in the mother and her baby, but also highlights potential avenues for intervention that may improve maternal-fetal outcomes during this critical period.

A greater understanding of critical periods of body weight regulation, including pregnancy, may aid in efforts to optimize weight management strategies for the mother and her baby. The gestational period has been implicated to play, in the child, a vital role in the developmental origins of obesity and other cardiometabolic diseases later in life. Therefore, we initially examined existing literature on the role of maternal obesity and its link to pediatric obesity and documented the known underlying physiological mechanisms responsible for this relationship while suggesting potential intervention targets that may improve maternal-fetal outcomes. In a second paper, we aimed to quantify maternal predictors of large for gestational age (LGA) neonates in the Ottawa and Kingston (OaK) birth cohort with specific hypotheses verifying the independent contribution of maternal prepregnancy body mass index (BMI) and excessive gestational weight gain (GWG) to fetal overgrowth. This paper also highlights the clinical utility of the revised 2009 Institute of Medicine GWG guidelines and discusses the potential role of physiological factors underlying the observed associations between BMI, excessive GWG and LGA neonates. As a follow-up to our population-level analysis (i.e., OAK cohort), papers three and four highlight how the insulin-like growth factor (IGF) axis, a vital regulator of growth and development, may be compromised at the molecular level in cases of maternal obesity (paper 3) and excessive GWG (paper 4). In paper 3 we show that maternal obesity is associated with attenuated expression of IGF binding protein-4 (IGFBP4) in umbilical cord blood and discuss how this may preferentially promote fetal adipogenesis. The effects of excessive GWG on IGF axis protein expression are addressed in paper four where we show that excessive weight gain during pregnancy is associated with increased expression of IGFBP3 in maternal circulation in normoglycemic term pregnancies. In this paper we discuss the potential inhibitory role of IGFBP3 on adipogenesis and how it relates to glucose intolerance during pregnancy. Recognizing that both obesity and excessive GWG can alter physiological processes in mother and her baby, appropriate evidence-based interventions are warranted to best optimize outcomes. In paper five, we discuss the results of a study which sought to assess patient information channels and knowledge of nutrition and physical activity during pregnancy with the intent that these findings be applied to best design efficacious strategies that cater to the needs of our target group of pregnant women. In our analysis we show that the majority of pregnant women studied would be willing to participate in a lifestyle intervention for their own personal health and that of their child. Of great interest was the observation that most women were not informed of the importance of pregnancy-specific energy intake, or made aware of their own healthy GWG targets. Additionally, many of the respondents reported receiving no information pertaining to appropriate physical activity recommendations; despite the fact that the vast majority of participants consider this lifestyle modality to be safe during their pregnancy. Finally in paper six, we build on the results of our previous work and evaluate the risks and benefits of physical activity during pregnancy on maternal-fetal outcomes through a review of the literature and note that engaging in non-sedentary pursuits during gestation may aid in maternal weight regulation, protect against metabolic disorders and optimize neonatal birth weight and body composition. Overall, the collective nature of the papers presented in this dissertation provides qualitative and quantitative evidence to support not only the complexity of body weight regulation in the mother and her baby, but also highlights potential avenues for intervention that may improve maternal-fetal outcomes during this critical period.