Existem evidências de que dietas compostas por níveis elevados de lipídeos e/ou car-boidratos contribuem para o desenvolvimento de doenças crônico-degenerativas e de déficit cognitivo. Entretanto, os mecanismos pelos quais a obesidade materna interfere na saúde da prole, especificamente no metabolismo e na memória de longo-prazo, ain-da são pouco claros. O objetivo deste trabalho foi investigar se a obesidade materna interfere no metabolismo e nos comportamentos relacionados à memória de longo-prazo de seus filhotes, e se há um efeito somatório com a exposição à dieta de cafete-ria no decorrer da vida da prole. Ratas foram alimentadas com dieta controle (CON) ou de cafeteria (CAF) desde o desmame até os 210 dias de vida, no desmame de sua pro-le. A partir do desmame, seus filhotes machos foram divididos em 4 grupos (CON-CON, CON-CAF, CAF-CON e CAF-CAF) para que todas as ninhadas ingerissem CON ou CAF, independentemente da dieta materna. As mães foram decapitadas no dia seguin-te ao desmame dos filhotes. Foi decapitada e analisada em tarefas comportamentais metade dos filhotes aos 30 dias de idade e, a outra metade, aos 120 dias. As mães CAF apresentaram maior peso corporal total e de tecido adiposo e maiores concentra-ções circulantes de colesterol total, insulina e leptina do que as mães CON. A ingestão calórica semanal dos filhotes que ingeriram CAF mostrou-se maior do que os que inge-riram CON, independentemente da dieta materna. As ninhadas apresentaram peso cor-poral igual no desmame e aos 30dias, porém aos 120dias, os filhotes que ingeriram CON-CAF tiveram aumento de peso em relação aos filhotes CON, independentemente da dieta materna destes. Porém, os filhotes CAF-CAF tiveram redução do peso corporal em relação aos CON-CAF na idade adulta. Aos 30 e 120 dias, os filhotes que ingeriram CAF apresentaram peso de tecido adiposo maior do que os que ingeriram CON, inde-pendentemente da dieta materna. Aos 30 e 120dias, a trigliceridemia e a colesterolemia estavam iguais entre os grupos, assim como a glicemia aos 30 dias. Porém, aos 120 dias, os filhotes que ingeriram CAF apresentaram hiperglicemia, assim como hiperlepti-nemia e hiperinsulinemia, independentemente da dieta materna. Aos 30 dias, todos os grupos que foram expostos à dieta de cafeteria em alguma etapa da vida apresentaram declínio no desempenho em uma ou nas duas tarefas relacionadas à memória de lon-go-prazo (Reconhecimento de objetos e Esquiva Inibitória step-down). Já aos 120 dias, o grupo CAF-CAF foi o único que mostrou piora no desempenho na tarefa de Reconhe-cimento de Objetos, e todos os grupos mostraram capacidade de aprendizado e memó-ria na tarefa de Esquiva Inibitória step-down. Esses dados sugerem que a dieta materna modula o peso corporal e comportamentos relacionados à memória de longo-prazo dos filhotes e que seus efeitos sofrem influência da dieta pós-natal da prole. Porém, novos estudos são necessários para elucidar os mecanismos envolvidos no desenvolvimento dessas alterações. / There is evidence that diets containing high levels of lipids and / or carbohydrates con-tribute to the development of chronic degenerative diseases and cognitive impairment. However, the mechanisms by which maternal obesity affects health of offspring, specifi-cally in metabolism and long-term memory, are still unclear. The aim of this study was to investigate whether maternal obesity interferes with the metabolism and behavior related to long-term memory of their offspring, and if there is a summation effect with exposure to the cafeteria diet during the life of the offspring. Rats were fed a control diet (CON) or cafeteria (CAF) from weaning to 210 days old at weaning of their offspring. After wean-ing, their male offspring were divided into 4 groups (CON-CON, CON-CAF, CAF and CAF-CON-CAF) for all litters ingest CON or CAF, irrespective of maternal diet. Mothers were decapitated on the day following weaning of pups. Was decapitated and analyzed in behavioral tasks half the pups at 30 days of age and the other half at 120 days. CAF mothers had higher total body weight and adipose tissue and increased circulating con-centrations of total cholesterol, insulin and leptin than mothers CON. The weekly caloric intake of pups that ingested CAF was higher than those who ate CON, regardless of maternal diet. Litters showed body weight equal to weaning and 30days, but the 120dias, puppies who ate CON-CAF had weight gain compared to CON offspring, re-gardless of maternal diet these. However, the pups CAF-CAF had reduced body weight compared to CON-CAF adulthood. At 30 and 120 days, the puppies that ingested CAF showed greater weight of adipose tissue than those who ate CON, irrespective of ma-ternal diet. At 30 and 120dias, blood triglyceride and cholesterol were similar between groups, as well as blood glucose levels at 30 days. However, at 120 days, the puppies that ingested CAF showed hyperglycemia, as hiperlepti-nemia and hyperinsulinemia, irrespective of maternal diet. At 30 days, all groups were exposed to the cafeteria diet at some stage of life show a decline in performance in one or both tasks related to long-term memory (Recognition of objects and Dodge inhibitory step-down). Already at 120 days, the group CAF-CAF was the one who showed deterioration in performance in the task of Object Recognition, and all groups showed learning ability and memory in the inhibitory avoidance task step down. These data suggest that maternal diet modulates body weight and behaviors related to long-term memory of the puppies and their effects are influenced by postnatal diet offspring. However, further studies are needed to eluci-date the mechanisms involved in the development of these changes.

Objetivo: Avaliar os efeitos da obesidade materna sobre a estrutura do pâncreas e metabolismo de carboidratos no início da vida adulta, com foco na prole da primeira geração (F1) e segunda geração (F2) de progenitoras F0 alimentadas com dieta rica em gordura nos períodos pré-gestacional, durante a gestação e lactação. Métodos: Camundongos C57BL/6 do gênero feminino (F0) foram alimentadas com dieta padrão (SC) ou dieta rica em gordura (HF) durante as oito semanas que antecederam o acasalamento, durante a gestação e lactação para gerar a F1 (F1-SC e F1-HF). As proles geradas receberam dieta SC até o terceiro mês de vida. Aos três meses de idade, fêmeas F1 foram acasaladas para gerar a F2 (F2-SC e F2-HF). Apenas os machos das geração F1 e F2 foram avaliados aos 3 meses de idade. As características metabólicas foram avaliadas pela massa corporal (MC), glicemia de jejum, área sob a curva no teste oral de tolerância a glicose; análise plasmática de insulina, leptina e adiponectina; distribuição e análise morfológica do pâncreas através da imunohistoquímica e imunofluorescência. Resultados: A prole F1-HF teve aumento significativo na massa corporal e glicemia quando comparado à F1-SC. Por outro lado, as proles F2-HF e F2-SC tiveram massas corporais semelhantes. A prole F1-HF e F2-HF mostrou aumento da ingestão de energia, intolerância à glicose, hiperinsulinemia, hiperleptinemia, hipoadiponectinemia, resistência à insulina, aumento da massa pancreática, o aumento da densidade de volume de ilhotas com elevada massa de células alfa e beta, ilhotas hipertrofiadas caracterizadas por uma distribuição alterada de células alfa e beta, e fraca imunoreatividade do pâncreas homeobox duodeno-1 (PDx1). Conclusões: Uma dieta HF materna consumida durante o período pré-concepção e durante toda a gestação e lactação em camundongos promoveu programação metabólica do pâncreas endócrino com pré-disposição ao diabetes mellitus tipo 2 precoce nas proles F1 e F2 do gênero masculino, sugerindo que essas mudanças são intergeracionais. / To evaluate the effects of maternal obesity upon pancreas structure and carbohydrate metabolism in early adult life, focusing on F1 and F2 generations of F0 dams fed high-fat diet during the pre-pregnancy, gestation, and lactation periods. Methods: C57BL/6 female mice (F0) were fed standard chow (SC) or HF diet for 8 weeks prior to mating and during gestation and lactation to provide F1 generation (F1-SC and F1-HF). At 3 months of age, F1 females were mated to produce F2 generation (F2-SC and F2-HF). Male offspring from all groups were evaluated at 3 months of age. Results: F1-HF offspring had significantly higher body mass and glycemia than F1-SC offspring. Conversely, F2-HF and F2-SC offspring had similar body masses. F1-HF and F2-HF offspring showed increased energy intake, glucose intolerance, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, insulin resistance, increased pancreatic mass, increased islet volume density with elevated alpha and beta cell mass, hypertrophied islets characterized by an altered distribution of alpha and beta cells, and weak pancreatic-duodenal homeobox (Pdx1) immunoreactivity. Conclusions: A maternal HF diet consumed during the preconception period and throughout the gestation and lactation in mice promotes metabolic and pancreatic programming in F1 and F2 male offspring, suggesting that these changes are intergenerational.

Objetivo: Avaliar os efeitos da obesidade materna sobre a estrutura do pâncreas e metabolismo de carboidratos no início da vida adulta, com foco na prole da primeira geração (F1) e segunda geração (F2) de progenitoras F0 alimentadas com dieta rica em gordura nos períodos pré-gestacional, durante a gestação e lactação. Métodos: Camundongos C57BL/6 do gênero feminino (F0) foram alimentadas com dieta padrão (SC) ou dieta rica em gordura (HF) durante as oito semanas que antecederam o acasalamento, durante a gestação e lactação para gerar a F1 (F1-SC e F1-HF). As proles geradas receberam dieta SC até o terceiro mês de vida. Aos três meses de idade, fêmeas F1 foram acasaladas para gerar a F2 (F2-SC e F2-HF). Apenas os machos das geração F1 e F2 foram avaliados aos 3 meses de idade. As características metabólicas foram avaliadas pela massa corporal (MC), glicemia de jejum, área sob a curva no teste oral de tolerância a glicose; análise plasmática de insulina, leptina e adiponectina; distribuição e análise morfológica do pâncreas através da imunohistoquímica e imunofluorescência. Resultados: A prole F1-HF teve aumento significativo na massa corporal e glicemia quando comparado à F1-SC. Por outro lado, as proles F2-HF e F2-SC tiveram massas corporais semelhantes. A prole F1-HF e F2-HF mostrou aumento da ingestão de energia, intolerância à glicose, hiperinsulinemia, hiperleptinemia, hipoadiponectinemia, resistência à insulina, aumento da massa pancreática, o aumento da densidade de volume de ilhotas com elevada massa de células alfa e beta, ilhotas hipertrofiadas caracterizadas por uma distribuição alterada de células alfa e beta, e fraca imunoreatividade do pâncreas homeobox duodeno-1 (PDx1). Conclusões: Uma dieta HF materna consumida durante o período pré-concepção e durante toda a gestação e lactação em camundongos promoveu programação metabólica do pâncreas endócrino com pré-disposição ao diabetes mellitus tipo 2 precoce nas proles F1 e F2 do gênero masculino, sugerindo que essas mudanças são intergeracionais. / To evaluate the effects of maternal obesity upon pancreas structure and carbohydrate metabolism in early adult life, focusing on F1 and F2 generations of F0 dams fed high-fat diet during the pre-pregnancy, gestation, and lactation periods. Methods: C57BL/6 female mice (F0) were fed standard chow (SC) or HF diet for 8 weeks prior to mating and during gestation and lactation to provide F1 generation (F1-SC and F1-HF). At 3 months of age, F1 females were mated to produce F2 generation (F2-SC and F2-HF). Male offspring from all groups were evaluated at 3 months of age. Results: F1-HF offspring had significantly higher body mass and glycemia than F1-SC offspring. Conversely, F2-HF and F2-SC offspring had similar body masses. F1-HF and F2-HF offspring showed increased energy intake, glucose intolerance, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, insulin resistance, increased pancreatic mass, increased islet volume density with elevated alpha and beta cell mass, hypertrophied islets characterized by an altered distribution of alpha and beta cells, and weak pancreatic-duodenal homeobox (Pdx1) immunoreactivity. Conclusions: A maternal HF diet consumed during the preconception period and throughout the gestation and lactation in mice promotes metabolic and pancreatic programming in F1 and F2 male offspring, suggesting that these changes are intergenerational.

Existem evidências de que dietas compostas por níveis elevados de lipídeos e/ou car-boidratos contribuem para o desenvolvimento de doenças crônico-degenerativas e de déficit cognitivo. Entretanto, os mecanismos pelos quais a obesidade materna interfere na saúde da prole, especificamente no metabolismo e na memória de longo-prazo, ain-da são pouco claros. O objetivo deste trabalho foi investigar se a obesidade materna interfere no metabolismo e nos comportamentos relacionados à memória de longo-prazo de seus filhotes, e se há um efeito somatório com a exposição à dieta de cafete-ria no decorrer da vida da prole. Ratas foram alimentadas com dieta controle (CON) ou de cafeteria (CAF) desde o desmame até os 210 dias de vida, no desmame de sua pro-le. A partir do desmame, seus filhotes machos foram divididos em 4 grupos (CON-CON, CON-CAF, CAF-CON e CAF-CAF) para que todas as ninhadas ingerissem CON ou CAF, independentemente da dieta materna. As mães foram decapitadas no dia seguin-te ao desmame dos filhotes. Foi decapitada e analisada em tarefas comportamentais metade dos filhotes aos 30 dias de idade e, a outra metade, aos 120 dias. As mães CAF apresentaram maior peso corporal total e de tecido adiposo e maiores concentra-ções circulantes de colesterol total, insulina e leptina do que as mães CON. A ingestão calórica semanal dos filhotes que ingeriram CAF mostrou-se maior do que os que inge-riram CON, independentemente da dieta materna. As ninhadas apresentaram peso cor-poral igual no desmame e aos 30dias, porém aos 120dias, os filhotes que ingeriram CON-CAF tiveram aumento de peso em relação aos filhotes CON, independentemente da dieta materna destes. Porém, os filhotes CAF-CAF tiveram redução do peso corporal em relação aos CON-CAF na idade adulta. Aos 30 e 120 dias, os filhotes que ingeriram CAF apresentaram peso de tecido adiposo maior do que os que ingeriram CON, inde-pendentemente da dieta materna. Aos 30 e 120dias, a trigliceridemia e a colesterolemia estavam iguais entre os grupos, assim como a glicemia aos 30 dias. Porém, aos 120 dias, os filhotes que ingeriram CAF apresentaram hiperglicemia, assim como hiperlepti-nemia e hiperinsulinemia, independentemente da dieta materna. Aos 30 dias, todos os grupos que foram expostos à dieta de cafeteria em alguma etapa da vida apresentaram declínio no desempenho em uma ou nas duas tarefas relacionadas à memória de lon-go-prazo (Reconhecimento de objetos e Esquiva Inibitória step-down). Já aos 120 dias, o grupo CAF-CAF foi o único que mostrou piora no desempenho na tarefa de Reconhe-cimento de Objetos, e todos os grupos mostraram capacidade de aprendizado e memó-ria na tarefa de Esquiva Inibitória step-down. Esses dados sugerem que a dieta materna modula o peso corporal e comportamentos relacionados à memória de longo-prazo dos filhotes e que seus efeitos sofrem influência da dieta pós-natal da prole. Porém, novos estudos são necessários para elucidar os mecanismos envolvidos no desenvolvimento dessas alterações. / There is evidence that diets containing high levels of lipids and / or carbohydrates con-tribute to the development of chronic degenerative diseases and cognitive impairment. However, the mechanisms by which maternal obesity affects health of offspring, specifi-cally in metabolism and long-term memory, are still unclear. The aim of this study was to investigate whether maternal obesity interferes with the metabolism and behavior related to long-term memory of their offspring, and if there is a summation effect with exposure to the cafeteria diet during the life of the offspring. Rats were fed a control diet (CON) or cafeteria (CAF) from weaning to 210 days old at weaning of their offspring. After wean-ing, their male offspring were divided into 4 groups (CON-CON, CON-CAF, CAF and CAF-CON-CAF) for all litters ingest CON or CAF, irrespective of maternal diet. Mothers were decapitated on the day following weaning of pups. Was decapitated and analyzed in behavioral tasks half the pups at 30 days of age and the other half at 120 days. CAF mothers had higher total body weight and adipose tissue and increased circulating con-centrations of total cholesterol, insulin and leptin than mothers CON. The weekly caloric intake of pups that ingested CAF was higher than those who ate CON, regardless of maternal diet. Litters showed body weight equal to weaning and 30days, but the 120dias, puppies who ate CON-CAF had weight gain compared to CON offspring, re-gardless of maternal diet these. However, the pups CAF-CAF had reduced body weight compared to CON-CAF adulthood. At 30 and 120 days, the puppies that ingested CAF showed greater weight of adipose tissue than those who ate CON, irrespective of ma-ternal diet. At 30 and 120dias, blood triglyceride and cholesterol were similar between groups, as well as blood glucose levels at 30 days. However, at 120 days, the puppies that ingested CAF showed hyperglycemia, as hiperlepti-nemia and hyperinsulinemia, irrespective of maternal diet. At 30 days, all groups were exposed to the cafeteria diet at some stage of life show a decline in performance in one or both tasks related to long-term memory (Recognition of objects and Dodge inhibitory step-down). Already at 120 days, the group CAF-CAF was the one who showed deterioration in performance in the task of Object Recognition, and all groups showed learning ability and memory in the inhibitory avoidance task step down. These data suggest that maternal diet modulates body weight and behaviors related to long-term memory of the puppies and their effects are influenced by postnatal diet offspring. However, further studies are needed to eluci-date the mechanisms involved in the development of these changes.

Existem evidências de que dietas compostas por níveis elevados de lipídeos e/ou car-boidratos contribuem para o desenvolvimento de doenças crônico-degenerativas e de déficit cognitivo. Entretanto, os mecanismos pelos quais a obesidade materna interfere na saúde da prole, especificamente no metabolismo e na memória de longo-prazo, ain-da são pouco claros. O objetivo deste trabalho foi investigar se a obesidade materna interfere no metabolismo e nos comportamentos relacionados à memória de longo-prazo de seus filhotes, e se há um efeito somatório com a exposição à dieta de cafete-ria no decorrer da vida da prole. Ratas foram alimentadas com dieta controle (CON) ou de cafeteria (CAF) desde o desmame até os 210 dias de vida, no desmame de sua pro-le. A partir do desmame, seus filhotes machos foram divididos em 4 grupos (CON-CON, CON-CAF, CAF-CON e CAF-CAF) para que todas as ninhadas ingerissem CON ou CAF, independentemente da dieta materna. As mães foram decapitadas no dia seguin-te ao desmame dos filhotes. Foi decapitada e analisada em tarefas comportamentais metade dos filhotes aos 30 dias de idade e, a outra metade, aos 120 dias. As mães CAF apresentaram maior peso corporal total e de tecido adiposo e maiores concentra-ções circulantes de colesterol total, insulina e leptina do que as mães CON. A ingestão calórica semanal dos filhotes que ingeriram CAF mostrou-se maior do que os que inge-riram CON, independentemente da dieta materna. As ninhadas apresentaram peso cor-poral igual no desmame e aos 30dias, porém aos 120dias, os filhotes que ingeriram CON-CAF tiveram aumento de peso em relação aos filhotes CON, independentemente da dieta materna destes. Porém, os filhotes CAF-CAF tiveram redução do peso corporal em relação aos CON-CAF na idade adulta. Aos 30 e 120 dias, os filhotes que ingeriram CAF apresentaram peso de tecido adiposo maior do que os que ingeriram CON, inde-pendentemente da dieta materna. Aos 30 e 120dias, a trigliceridemia e a colesterolemia estavam iguais entre os grupos, assim como a glicemia aos 30 dias. Porém, aos 120 dias, os filhotes que ingeriram CAF apresentaram hiperglicemia, assim como hiperlepti-nemia e hiperinsulinemia, independentemente da dieta materna. Aos 30 dias, todos os grupos que foram expostos à dieta de cafeteria em alguma etapa da vida apresentaram declínio no desempenho em uma ou nas duas tarefas relacionadas à memória de lon-go-prazo (Reconhecimento de objetos e Esquiva Inibitória step-down). Já aos 120 dias, o grupo CAF-CAF foi o único que mostrou piora no desempenho na tarefa de Reconhe-cimento de Objetos, e todos os grupos mostraram capacidade de aprendizado e memó-ria na tarefa de Esquiva Inibitória step-down. Esses dados sugerem que a dieta materna modula o peso corporal e comportamentos relacionados à memória de longo-prazo dos filhotes e que seus efeitos sofrem influência da dieta pós-natal da prole. Porém, novos estudos são necessários para elucidar os mecanismos envolvidos no desenvolvimento dessas alterações. / There is evidence that diets containing high levels of lipids and / or carbohydrates con-tribute to the development of chronic degenerative diseases and cognitive impairment. However, the mechanisms by which maternal obesity affects health of offspring, specifi-cally in metabolism and long-term memory, are still unclear. The aim of this study was to investigate whether maternal obesity interferes with the metabolism and behavior related to long-term memory of their offspring, and if there is a summation effect with exposure to the cafeteria diet during the life of the offspring. Rats were fed a control diet (CON) or cafeteria (CAF) from weaning to 210 days old at weaning of their offspring. After wean-ing, their male offspring were divided into 4 groups (CON-CON, CON-CAF, CAF and CAF-CON-CAF) for all litters ingest CON or CAF, irrespective of maternal diet. Mothers were decapitated on the day following weaning of pups. Was decapitated and analyzed in behavioral tasks half the pups at 30 days of age and the other half at 120 days. CAF mothers had higher total body weight and adipose tissue and increased circulating con-centrations of total cholesterol, insulin and leptin than mothers CON. The weekly caloric intake of pups that ingested CAF was higher than those who ate CON, regardless of maternal diet. Litters showed body weight equal to weaning and 30days, but the 120dias, puppies who ate CON-CAF had weight gain compared to CON offspring, re-gardless of maternal diet these. However, the pups CAF-CAF had reduced body weight compared to CON-CAF adulthood. At 30 and 120 days, the puppies that ingested CAF showed greater weight of adipose tissue than those who ate CON, irrespective of ma-ternal diet. At 30 and 120dias, blood triglyceride and cholesterol were similar between groups, as well as blood glucose levels at 30 days. However, at 120 days, the puppies that ingested CAF showed hyperglycemia, as hiperlepti-nemia and hyperinsulinemia, irrespective of maternal diet. At 30 days, all groups were exposed to the cafeteria diet at some stage of life show a decline in performance in one or both tasks related to long-term memory (Recognition of objects and Dodge inhibitory step-down). Already at 120 days, the group CAF-CAF was the one who showed deterioration in performance in the task of Object Recognition, and all groups showed learning ability and memory in the inhibitory avoidance task step down. These data suggest that maternal diet modulates body weight and behaviors related to long-term memory of the puppies and their effects are influenced by postnatal diet offspring. However, further studies are needed to eluci-date the mechanisms involved in the development of these changes.

INTRODUCCIÓN: la revisión de la literatura científica evidencia controversia con respecto a la relación entre el estado de sobrepeso/obesidad materna (S/O) y el estado de sobrepeso/obesidad (S/O) en sus hijos adolescentes. OBJETIVO: determinar si existe relación entre el antecedente de sobrepeso/obesidad de la madre durante la primera infancia del niño y el desarrollo de la sobrepeso/obesidad en la adolescencia, considerando el potencial rol de variables confusoras (como, edad, sexo, nivel socioeconómico, nivel educativo de la madre, actividad física del niño y tipo de migración). MATERIALES Y MÉTODOS: Análisis de base de datos secundaria de una cohorte proveniente de un estudio longitudinal multinacional ("base de datos Young Lives -YL"), específicamente de Perú compuesta por 1431 adolescentes, a quienes se evaluó el antecedente de sobrepeso/obesidad de la madre (1ra ronda), estado de sobrepeso/obesidad en la adolescencia (5ta ronda y las variables confusoras: sexo (1ra ronda), edad, nivel socioeconómico, nivel educativo de la madre, actividad física del niño y tipo de migración (5ta ronda) a través del modelo estadístico Regresión de Poisson. RESULTADOS: La prevalencia del estado de sobrepeso/obesidad en las madres y adolescentes fue 42,4% y 25% respectivamente; tanto el análisis de Poisson simple y múltiple, mostraron asociación entre el estado materno S/O y ​​el estado S/O en la descendencia adolescente (RRc= 1,3; IC al 95%: 1,1 al 1,5; p <0,001 y RRa= 1,2; IC al 95%: 1,1 al 1,4; p = 0,031, respectivamente). CONCLUSIONES: se encontró una relación significativa entre el estado materno S/O y el estado S/O del adolescente en la población estudiada después del ajuste por terceras variables como edad, sexo, nivel socioeconómico, nivel educativo de la madre, actividad física adolescente y tipo de migración. / Does maternal overweight/obesity status during offspring´s early childhood influence in the development of overweight/obesity status at an adolescence age?, results of the analysis of the younger cohort (2002-2016) of Young Lives, in Peru / Tesis

L'obésité maternelle peut prédisposer aux pathologies métaboliques à l'âge adulte. Une perte de poids préconceptionnelle est recommandée aux femmes obèses, mais ses effets sur la croissance fœto-placentaire et la santé de la descendance adulte sont encore peu connus. Les objectifs de cette thèse étaient d’étudier les effets des trajectoires pondérales maternelles sur le phénotype de la descendance à terme et à l’âge adulte, ainsi que sur l’expression génique. Les descendants de mères obèses présentent une restriction de croissance fœtale, associée à des altérations d’expression des gènes de la machinerie épigénétique dans le foie fœtal et le labyrinthe placentaire. Notre étude souligne la sensibilité particulière de la machinerie d’acétylation des histones au métabolisme maternel. À l'âge adulte, les mâles nés des mères obèses développent une obésité aggravée lorsqu'ils sont exposés à un environnement obésogène. La perte de poids maternelle préconceptionnelle améliore la croissance fœtale et normalise le poids à l’âge adulte. Elle est donc bénéfique pour la descendance. Cependant, certains effets de l’obésité, corrigée par l’intervention nutritionnelle, sont conservés car le poids fœtal et l’expression d’une partie de gènes restent altérés. Ce travail apporte des premiers éléments sur les mécanismes du conditionnement développemental par les trajectoires pondérales maternelles. / Maternal obesity (OB) impacts fetal growth and adult offspring phenotype. It is still unknown whether the currently recommended preconceptional weight loss (WL) for obese women is beneficial for feto-placental growth and adult offspring health. The objectives of this thesis were to assess the effects of maternal weight trajectories on offspring phenotype at term and in adulthood, as well as gene expression in placenta and fetal liver. At E18.5, fetuses from obese females presented a fetal growth restriction (FGR); this FGR was almost completely abolished by maternal WL. Placental and hepatic expression of epigenetic machinery genes was affected by maternal OB, especially the histone acetylation pathway. Maternal WL normalized the expression of only a subset of these genes. Males born to OB mothers gained weight faster under high-fat diet than males born to control mothers; maternal WL rescued this phenotype. These results show that expression of epigenetic machinery genes and in particular histone acetylation regulators, is highly sensitive to maternal obesity. Preconceptional WL alleviates the effects of OB on fetal and adult weight but some effects of obesity cured by nutritional intervention were retained in offspring phenotype at term. This study is an important step toward understanding the mechanisms linking maternal nutrition to fetal growth and adult health.

L’objectif de cette thèse était de mesurer l’association de l’obésité maternelle avec la durée de l’allaitement maternel, au total et exclusif, en prenant en compte les caractéristiques sociodémographiques, périnatales et psychosociales ; puis d’évaluer si l’allaitement était, en France en 2012, associé à une diminution de la rétention du poids maternel dans l’année suivant l’accouchement, en particulier chez les femmes obèses.Les données de la cohorte prospective nationale Epifane ont été utilisées. En 2012, 3368 couples mère-enfant avaient été inclus en France métropolitaine. Le recueil de l’alimentation de l’enfant à la maternité puis à 1, 4, 8 et 12 mois postpartum a permis d’estimer les durées d’allaitement. Les facteurs sociodémographiques et périnataux associés à l’obésité maternelle (Indice de Masse Corporelle (IMC) avant grossesse ≥30 kg/m2) ont été identifiés par un modèle de régression logistique multinomiale. Des régressions de Poisson ont fourni des estimations de l’association entre obésité et durées d’allaitement, exclusif et total. Les associations entre durées d’allaitement et rétention de poids à 4 et 12 mois (définie comme la différence entre le poids maternel à 4 et 12 mois et le poids avant grossesse), ont été estimées par des régressions linéaires. Les facteurs de risque d’une rétention de poids modeste (entre 0,1 et 4,9 kg) ou majeure (≥5 kg) à un an, ont été identifiés par des régressions logistiques multinomialesL’obésité maternelle était associée à un ensemble de caractéristiques sociodémographiques et de complications périnatales, de façon différente selon la parité. Par ailleurs, elle était associée à une durée totale d’allaitement plus courte, comparé à une corpulence normale, indépendamment des caractéristiques sociodémographiques, périnatales, psychosociales, et de la parité. La parité modifiait l’association entre obésité et durée d’allaitement exclusif. Ainsi, chez les primipares, la durée d’allaitement exclusif était comparable chez les femmes obèses et celles de corpulence normale, quel que soit le niveau d’ajustement. Chez les multipares, la relation entre obésité maternelle et durée d’allaitement exclusif réduite observée dans le modèle ajusté sur les caractéristiques sociodémographiques, n’était plus significative lorsque les caractéristiques périnatales et psychosociales étaient ajoutées au modèle.A 4 mois, dans tous les groupes d’IMC avant grossesse, la rétention moyenne de poids postpartum n’était pas différente selon la durée d’allaitement exclusif ou prédominant. Néanmoins, la durée d’allaitement mixte était associée à une augmentation de la rétention de poids à 4 mois, chez les femmes obèses uniquement. A 12 mois, ni la durée d’allaitement exclusif ou prédominant, ni celle d’allaitement mixte n’étaient associées à la rétention de poids. Les risques d’une rétention de poids modeste ou majeure une année après avoir accouché, variaient toutefois selon un ensemble de caractéristiques sociodémographiques et périnatales. La durée totale d’allaitement maternel était plus faible chez les femmes obèses. Par ailleurs, nos travaux ne montrent pas un bénéfice de l’allaitement sur la diminution de la rétention de poids à 4 et 12 mois. Finalement, nos travaux apportent une meilleure compréhension des mécanismes impliqués dans la relation entre obésité et allaitement maternel ; l’identification des facteurs de risque de la rétention de poids ouvre de nombreuses perspectives de recherche. En termes de santé publique, ces travaux réaffirment la nécessité de prendre en compte les facteurs psychosociaux, les caractéristiques sociodémographiques, et les conditions de la grossesse dans la promotion de l’allaitement, notamment exclusif, et dans les actions visant à réduire la rétention de poids postpartum. / The aim of this PhD dissertation was to measure the association of maternal obesity with any breastfeeding (ABF), and exclusive breastfeeding (EBF) durations, taking into account sociodemographic, perinatal and psychosocial factors; and to assess whether in France, in 2012, breasfeeding was associated with a reduction in PPWR during the first year of life, especially among women obese before pregnancy.We used data from the French population-based-birth-cohort Epifane. In 2012, 3,368 mother-infant dyads were included in mainland France. Information concerning infant’s feeding were collected at maternity ward and at 1, 4, 8, and 12 months, and were then used to define breastfeeding durations. Sociodemographic and perinatal factors associated with maternal obesity (Body Mass Index (BMI) before pregnancy ≥30 kg/m2) were identified using a multinomial logistic regression model. Poisson regression models have estimated associations of maternal obesity with ABF and EBF durations. Linear regression models were used to estimate the associations of breastfeeding durations (full breastfeeding (FBF) and partial breastfeeding) with PPWR at 4 and 12 months (defined as the difference between the maternal weight at 4 and 12 months after birth and maternal prepregnancy weight). Risk factors of moderate PPWR (0.1-4.9 kg) and major PPWR (≥5 kg) at 12 months were identified using multinomial logistic regression modelling.Maternal obesity was associated with sociodemographic characteristics and adverse perinatal outcomes. Such patterns varied among primiparous and multiparous women. Furthermore, maternal obesity was associated with a reduced ABF duration, compared to normal-weight, independently of sociodemographic, perinatal and psychosocial factors, and parity. Association of maternal obesity with EBF duration was modified by parity. Among primiparous women, obese women exclusively breastfed as long as normal-weight women, in all adjusted models. Among multiparous women, association between maternal obesity and reduced EBF duration, observed in the crude model and model adjusted on sociodemographic factors, was no more statistically significant when adjusting for perinatal and psychosocial factors.Four months after birth, FBF duration was not associated with PPWR, regardless of prepregnancy BMI class. However, partial breastfeeding duration was associated with an increased PPWR at 4 months among women obese before pregnancy. At 12 months, neither FBF duration nor partial breastfeeding duration was associated with PPWR. Nevertheless, we identified a set of sociodemographic and perinatal risk factors of moderate and major PPWR at 12 months.Maternal obesity was associated with a reduced ABF duration. Furthermore, our work does not confirm the hypothesis of a benefit of breastfeeding durations on PPWR at 4 and 12 months. Finally, our research provides a better understanding of mechanisms involved in the relation between maternal obesity and breastfeeding; the identification of PPWR risk factors opens new prospects of research. In terms of public health, our research reinforces the need to consider sociodemographic, perinatal and psychosocial characterictics of women in the promotion of breastfeeding, especially EBF, and in the interventions aimed at reducing PPWR.

Trajectoires développementales de l’IMC durant l’enfance: Une étude longitudinale sur 8 ans. Introduction : L’obésité infantile, origine de nombreux problèmes de santé, représente un grand défi en santé publique. Récemment, l’importance d’étudier l’évolution du surpoids durant l’enfance ainsi que les facteurs de risques précoces pour l’obésité a été reconnue. Les trajectoires développementales d’indice de masse corporelle (IMC) chez les jeunes représentent une approche innovatrice qui nous permet de mieux comprendre cette problématique importante. Objectifs: 1) Identifier des trajectoires développementales distinctes de groupes d’enfants selon leur IMC durant l’enfance, et 2) Explorer les facteurs de risques précoces qui prédisent l’appartenance de l’enfant à la trajectoire d’IMC le plus élevé Hypothèses: 1) On s’attend à retrouver un groupe d’enfants qui suit une trajectoire d’IMC élevée durant l’enfance. 2) On s’attend à ce que certaines caractéristiques de la mère (ex : tabac pendant la grossesse et IMC élevé), soient associées à l’appartenance de l’enfant au groupe ayant la trajectoire «IMC élevé ». Méthodes: Estimation des trajectoires développementales d’IMC d’enfants, dans un échantillon populationnel (n=1957) au Québec (ELDEQ). Les IMC ont été calculés à partir de données fournies par les mères des enfants et recueillis chaque année sur une durée de 8 ans. Des données propres à l’enfant sa mère, ainsi que socioéconomiques, ont étés recueillies. Une régression logistique multinomiale a été utilisée pour distinguer les enfants avec un IMC élevé des autres enfants, selon les facteurs de risques précoces. Les programmes PROC TRAJ (extension de SAS), SPSS (version 16), et SAS (version 9.1.3) ont été utilisés pour ces analyses. Résultats: Trois trajectoires d’IMC ont étés identifiées : IMC « bas-stable » (54,5%), IMC « modéré » (41,0%) et IMC « élevé et en hausse » (4,5%). Le groupe « élevé et en hausse » incluait des enfants pour qui l’IMC à 8 ans dépassait la valeur limite pour l’obésité. Les analyses de régression logistique ont révélé que deux facteurs de risques maternels étaient significativement associés avec la trajectoire “en hausse” par rapport aux deux autres groupes : le tabac durant la grossesse et le surpoids maternel. Conclusions: Des risques d’obésité infantile peuvent êtres identifiés dès la grossesse. Des études d’intervention sont requises pour identifier la possibilité de réduire le risque d’obésité chez l’enfant en ciblant le tabac et le surpoids maternelle durant la grossesse. Mots clés: Indice de masse corporelle (IMC), obésité infantile, trajectoires développementales de groupe, facteurs de risque précoce, étude populationnelle, tabac pendant la grossesse, obésité maternelle. / Developmental Trajectories of Body Mass Index in Early Childhood: An 8-Year Longitudinal Study. Introduction: Childhood obesity has become one of the greatest Public Health challenges this century, affecting not only developed nations, but increasingly low- and middle-income countries as well. Estimating developmental trajectories of Body Mass Index (BMI) during early childhood represents an innovative approach towards a better understanding of the development of this health problem. Objective: To identify groups of children with distinct developmental trajectories of Body Mass Index (BMI) between the ages of five months and eight years, and to identify early-life risk factors that distinguish children in an atypically elevated BMI trajectory group. Methods: Group-based developmental trajectories of BMI were estimated from annual maternal assessments (5 months to 8 years) in a large population sample (n=1957). Measures of height and weight, as well as family and child characteristics were obtained yearly from mothers. Multivariate logistic regression was used to distinguish children with elevated BMI from other children, using pre and early post-natal risk factors. Results: Three trajectories of BMI were identified: low-stable BMI (54.5%), moderate BMI (41.0%) and high-rising BMI (4.5%). The high-rising group included children whose BMI, at eight years of age, exceeded the cut-off value for obesity. Multinomial logit regression analyses revealed that two maternal risk factors were significantly associated with the high-rising BMI trajectory group as compared to both the low and moderate groups: smoking during pregnancy and maternal overweight. Conclusions: Antecedents of childhood obesity can be identified during pregnancy. Intervention studies are needed in order to test the possibility that targeting maternal smoking and maternal obesity during pregnancy would reduce the risk of childhood obesity in the offspring. Keywords: Body Mass Index (BMI), child obesity, Group-based developmental trajectories, early life predictors, population-based study, maternal smoking, maternal obesity.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O objetivo do presente estudo foi avaliar se o Bezafibrato, um agonista PAN-PPAR, é capaz de aliviar a doença não alcoólica do fígado gorduroso (NAFLD) na prole de machos de mães C57BL/6 obesas. Fêmeas virgens foram alimentadas com uma dieta HL (hiperlipídica, 49% de lipídios) ou uma dieta C (controle, 10% de lipídios) por oito semanas antes do acasalamento e durante os períodos de gestação e lactação. A prole de machos foi subdividida em quatro grupos: C (dieta controle para as mães e filhotes); C/BZ (dieta controle para as mães e filhotes com tratamento com Bezafibrato[100mg/Kg]); HL (dieta HL para as mães e dieta controle para os filhotes); e HL/BZ (dieta HL para as mães e dieta controle para os filhotes com tratamento com Bezafibrato [100mg/Kg]). O tratamento com Bezafibrato começou na 12 semana e se manteve por três semanas. Análise do metabolismo, bioquímica, estereológica e por western-blotting foram realizadas. A dieta HL causou um fenótipo de sobrepeso nas mães e acarretou em uma intolerância oral à glicose com aumento da glicemia de jejum. A prole HL apresentou hiperfagia, ganho de massa corporal, altos níveis de triglicerídeo hepático e plasmático, esteatose hepática e aumento da expressão de proteínas lipogênicas concomitante com diminuição do receptor ativador de proliferação peroxissomal alfa (PPAR&#945;), que é responsável pela &#946;-oxidação e aumento do receptor ativador de proliferação peroxissomal gama (PPAR&#947;) e do elemento regulador de esterol ligante da proteína 1 (SREBP-1c) proteínas envolvidas na lipogênese hepática. Por outro lado, o tratamento com o Bezafibrato reverteu o quadro da programação metabólica no fígado, com uma melhora dos parâmetros morfológicos, bioquímicos e moleculares do fígado dos animais, com um aumento da ativação de PPAR&#945; em associação a uma diminuição do PPAR&#947; e não alterando a expressão de SREBP-1c. Em conclusão, nós demonstramos que o tratamento com Bezafibrato melhora a NAFLD causada pela obesidade materna. / The aim of the present study was to evaluate whether Bezafibrate , a PAN-PPAR agonist, could attenuate non-alcoholic fatty liver disease (NAFLD) of male offspring from obese C57BL/6 dams. Dams were fed on a HF (high-fat, 49% lipids) diet or SC (standard chow; 10% lipids) diet for 8 weeks before mating and during gestation and lactation periods. Male offspring were subdivided into 4 groups: SC (standard-chow for dams and offspring); SC/BZ [standard-chow for dams and offspring with treatment with BZ (100mg/Kg)]; HF (high-fat diet for dams and standard-chow for offspring); HF/BZ [high-fat diet for dams and standard-show for offspring with treatment with Bezafibrate (100mg/Kg)]. Treatment with Bezafibrate started at 12th week and was maintained for 3 weeks. Metabolic measurements, biochemical analysis, stereological tools and western-blotting were performed. The HF diet yielded an overweight phenotype and an increase in oral glucose tolerance and fasting glucose of dams. The HF offspring presented hyperphagia, body mass gain, high levels of plasmatic and hepatic triglycerides, impairment of glucose metabolism, hepatic steatosis and high expression of lipogenic proteins concomitant to decreased expression of PPAR&#945;, which is responsible for &#946;-oxidation. On the other hand, treatment with Bezafibrate reverted hepatic outcomes of metabolic programming, with an improvement of morphological, biochemical and molecular parameters of animals livers, with an increase of PPAR&#945; activation in association with a decrease of PPAR&#947; expression and no changes in SREBP-1c expression. In conclusion, we demonstrated that treatment with Bezafibrate improved NAFLD caused by maternal obesity.