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1.
Am J Physiol Endocrinol Metab ; 317(6): E1094-E1107, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31638854

RESUMO

Clinical and animal studies have reported an association between low birth weight and the development of nonalcoholic fatty liver disease (NAFLD) in offspring. Using a model of prenatal maternal 70% food restriction diet (FR30) in the rat, we previously showed that maternal undernutrition predisposes offspring to altered lipid metabolism in adipose tissue, especially on a high-fat (HF) diet. Here, using microarray-based expression profiling combined with metabolic, endocrine, biochemical, histological, and lipidomic approaches, we assessed whether FR30 procedure sensitizes adult male offspring to impaired lipid metabolism in the liver. No obvious differences were noted in the concentrations of triglycerides, cholesterol, and bile acids in the liver of 4-mo-old FR30 rats whichever postweaning diet was used. However, several clues suggest that offspring's lipid metabolism and steatosis are modified by maternal undernutrition. First, lipid composition was changed (i.e., higher total saturated fatty acids and lower elaidic acid) in the liver, whereas larger triglyceride droplets were observed in hepatocytes of undernourished rats. Second, FR30 offspring exhibited long-term impact on hepatic gene expression and lipid metabolism pathways on a chow diet. Although the transcriptome profile was globally modified by maternal undernutrition, cholesterol and bile acid biosynthesis pathways appear to be key targets, indicating that FR30 animals were predisposed to impaired hepatic cholesterol metabolism. Third, the FR30 protocol markedly modifies hepatic gene transcription profiles in undernourished offspring in response to postweaning HF. Overall, FR30 offspring may exhibit impaired metabolic flexibility, which does not enable them to properly cope with postweaning nutritional challenges influencing the development of nonalcoholic fatty liver.


Assuntos
Fígado Gorduroso/genética , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Desnutrição , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Perfilação da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Gotículas Lipídicas/patologia , Fígado/patologia , Masculino , Ácidos Oleicos/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Fenômenos Fisiológicos da Nutrição Pré-Natal/genética , Ratos , Triglicerídeos/metabolismo
2.
Int J Obes (Lond) ; 43(12): 2381-2393, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30622312

RESUMO

OBJECTIVE: The lactation-suckling period is critical for white adipose tissue (WAT) development. Early postnatal nutrition influences later obesity risk but underlying mechanisms remain elusive. Here, we tested whether altered postnatal nutrition specifically during suckling impacts epigenetic regulation of key metabolic genes in WAT and alter long-term adiposity set point. METHODS: We analyzed the effects of maternal high-fat (HF) feeding in rats exclusively during lactation-suckling on breast milk composition and its impact on male offspring visceral epidydimal (eWAT) and subcutaneous inguinal (iWAT) depots during suckling and in adulthood. RESULTS: Maternal HF feeding during lactation had no effect on mothers' body weight (BW) or global breast milk composition, but induced qualitative changes in breast milk fatty acid (FA) composition (high n-6/n-3 polyunsaturated FA ratio and low medium-chain FA content). During suckling, HF neonates showed increased BW and mass of both eWAT and iWAT depot but only eWAT displayed an enhanced adipogenic transcriptional signature. In adulthood, HF offspring were predisposed to weight gain and showed increased hyperplastic growth only in eWAT. This specific eWAT expansion was associated with increased expression and activity of stearoyl-CoA desaturase-1 (SCD1), a key enzyme of FA metabolism. SCD1 converts saturated FAs, e.g. palmitate and stearate, to monounsaturated FAs, palmitoleate and oleate, which are the predominant substrates for triglyceride synthesis. Scd1 upregulation in eWAT was associated with reduced DNA methylation in Scd1 promoter surrounding a PPARγ-binding region. Conversely, changes in SCD1 levels and methylation were not observed in iWAT, coherent with a depot-specific programming. CONCLUSIONS: Our data reveal that maternal HF feeding during suckling programs long-term eWAT expansion in part by SCD1 epigenetic reprogramming. This programming events occurred with drastic changes in breast milk FA composition, suggesting that dietary FAs are key metabolic programming factors in the early postnatal period.


Assuntos
Tecido Adiposo Branco , Dieta Hiperlipídica , Epigênese Genética/genética , Lactação/genética , Estearoil-CoA Dessaturase , Tecido Adiposo Branco/química , Tecido Adiposo Branco/enzimologia , Tecido Adiposo Branco/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal/genética , Feminino , Gordura Intra-Abdominal/química , Gordura Intra-Abdominal/enzimologia , Gordura Intra-Abdominal/metabolismo , Masculino , Leite/química , Ratos Wistar , Estearoil-CoA Dessaturase/análise , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
3.
FASEB J ; 32(5): 2768-2778, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29295860

RESUMO

According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates program obesity later in life. White adipose tissue (WAT) has been the focus of developmental programming events, although underlying mechanisms remain elusive. In rodents, WAT development primarily occurs during lactation. We previously reported that adult rat offspring from dams fed a high-fat (HF) diet exhibited fat accumulation and decreased peroxisome proliferator-activated receptor γ (PPARγ) mRNA levels in WAT. We hypothesized that PPARγ down-regulation occurs via epigenetic malprogramming which takes place during adipogenesis. We therefore examined epigenetic modifications in the PPARγ1 and PPARγ2 promoters in perirenal (pWAT) and inguinal fat pads of HF offspring at weaning (postnatal d 21) and in adulthood. Postnatal d 21 is a period characterized by active epigenomic remodeling in the PPARγ2 promoter (DNA hypermethylation and depletion in active histone modification H3ac and H3K4me3) in pWAT, consistent with increased DNA methyltransferase and DNA methylation activities. Adult HF offspring exhibited sustained hypermethylation and histone modification H3ac of the PPARγ2 promoter in both deposits, correlated with persistent decreased PPARγ2 mRNA levels. Consistent with the DOHaD hypothesis, retained epigenetic marks provide a mechanistic basis for the cellular memory linking maternal obesity to a predisposition for later adiposity.-Lecoutre, S., Pourpe, C., Butruille, L., Marousez, L., Laborie, C., Guinez, C., Lesage, J., Vieau, D., Eeckhoute, J., Gabory, A., Oger, F., Eberlé, D., Breton, C. Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications.


Assuntos
Tecido Adiposo/metabolismo , Metilação de DNA , Epigênese Genética , Obesidade/metabolismo , PPAR gama/biossíntese , Regiões Promotoras Genéticas , Tecido Adiposo/patologia , Adiposidade/genética , Animais , Feminino , Histonas/genética , Histonas/metabolismo , Masculino , Obesidade/genética , PPAR gama/genética , Processamento de Proteína Pós-Traducional , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar
4.
Eur J Nutr ; 58(6): 2411-2423, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30167852

RESUMO

PURPOSE: Poor maternal nutrition sensitises to the development of metabolic diseases and obesity in adulthood over several generations. The prevalence increases when offspring is fed with a high-fat (HF) diet after weaning. This study aims to determine whether such metabolic profiles can be transmitted to the second generation and even aggravated when the mothers were exposed to overnutrition, with attention to potential sex differences. METHODS: Pregnant Wistar rats were subjected to ad libitum (control) or 70% food-restricted diet (FR) during gestation (F0). At weaning, F1 females were allocated to three food protocols: (1) standard diet prior to and throughout gestation and lactation, (2) HF diet prior to and standard diet throughout gestation and lactation, and (3) HF diet prior to and throughout gestation and lactation. F2 offspring was studied between 16 and 32 weeks of age. RESULTS: FR-F2 offspring on standard diet showed normal adiposity and had no significant metabolic alterations in adulthood. Maternal HF diet resulted in sex-specific effects with metabolic disturbances more apparent in control offspring exposed to HF diet during gestation and lactation. Control offspring displayed glucose intolerance associated with insulin resistance in females. Female livers overexpressed lipogenesis genes and those of males the genes involved in lipid oxidation. Gene expression was significantly attenuated in the FR livers. Increased physical activity associated with elevated corticosterone levels was observed in FR females on standard diet and in all females from overnourished mothers. CONCLUSIONS: Maternal undernutrition during gestation (F0) improves the metabolic health of second-generation offspring with more beneficial effects in females.


Assuntos
Dieta/métodos , Fígado/metabolismo , Fígado/fisiopatologia , Desnutrição/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Animais , Animais Recém-Nascidos , Dieta Hiperlipídica/métodos , Modelos Animais de Doenças , Feminino , Masculino , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Mães , Gravidez , Ratos , Ratos Wistar , Fatores Sexuais , Desmame
5.
Am J Physiol Endocrinol Metab ; 301(3): E548-59, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21712534

RESUMO

Several studies have shown that maternal undernutrition leading to low birth weight predisposes offspring to the development of metabolic pathologies such as obesity. Using a model of prenatal maternal 70% food restriction diet (FR30) in rat, we evaluated whether postweaning high-fat (HF) diet would amplify the phenotype observed under standard diet. We investigated biological parameters as well as gene expression profile focusing on white adipose tissues (WAT) of adult offspring. FR30 procedure does not worsen the metabolic syndrome features induced by HF diet. However, FR30HF rats displayed catch-up growth to match the body weight of adult control HF animals, suggesting an increase of adiposity while showing hyperleptinemia and a blunted increase of corticosterone. Using quantitative RT-PCR array, we demonstrated that FR30HF rats exhibited leptin and Ob-Rb as well as many peptide precursor and receptor gene expression variations in WAT. We also showed that the expression of genes involved in adipogenesis was modified in FR30HF animals in a depot-specific manner. We observed an opposite variation of STAT3 phosphorylation levels, suggesting that leptin sensitivity is modified in WAT adult FR30 offspring. We demonstrated that 11ß-HSD1, 11ß-HSD2, GR, and MR genes are coexpressed in WAT and that FR30 procedure modifies gene expression levels, especially under HF diet. In particular, level variation of 11ß-HSD2, whose protein expression was detected by Western blotting, may represent a novel mechanism that may affect WAT glucocorticoid sensitivity. Data suggest that maternal undernutrition differently programs the adult offspring WAT gene expression profile that may predispose for altered fat deposition.


Assuntos
Tecido Adiposo/metabolismo , Gorduras na Dieta/metabolismo , Desnutrição/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Adiposidade/efeitos dos fármacos , Adiposidade/genética , Animais , Peso Corporal/genética , Feminino , Expressão Gênica , Leptina/genética , Leptina/metabolismo , Masculino , Desnutrição/genética , Obesidade/genética , Obesidade/metabolismo , Fosforilação , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
6.
Am J Physiol Regul Integr Comp Physiol ; 299(1): R101-10, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20463183

RESUMO

Several studies indicate that maternal undernutrition sensitizes the offspring to the development of metabolic disorders, such as obesity. Using a model of perinatal maternal 50% food-restricted diet (FR50), we recently reported that rat neonates from undernourished mothers exhibit decreased leptin plasma levels associated with alterations of hypothalamic proopiomelanocortin system. The present study aimed at examining the consequences of FR50 on the brain-adipose axis in male rat neonates. Using quantitative RT-PCR array containing 84 obesity-related genes, we demonstrated that most of the genes involved in energy metabolism regulation are expressed in rat gonadal white adipose tissue (WAT) and are sensitive to maternal perinatal undernutrition (MPU). In contrast, hypothalamic gene expression was not substantially affected by MPU. Gene expression of uncoupling protein 1 (UCP1), a marker of brown adipocytes, showed an almost 400-fold stimulation in postnatal day 21 (PND21) FR50 animals, suggesting that their gonadal WAT possesses a brown-like phenotype. This was confirmed by histological and immunoshistochemical procedures, which demonstrated that PND21 FR50 gonadal adipocytes are multilocular, resembling those present in interscapular brown adipose tissue, and exhibit an overexpression of UCP1 and neuropeptide Y (NPY) at the protein level. Control animals contained almost exclusively "classical" unilocular white adipocytes that did not show high UCP1 and NPY labeling. After weaning, FR50 animals exhibited a transient hyperphagia that was associated with the disappearance of brown-like fat pads in PND30 WAT. Our results demonstrate that MPU delays the maturation of gonadal WAT during critical developmental time windows, suggesting that it could have long-term consequences on body weight regulation in the offspring.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo/metabolismo , Desnutrição , Adipócitos/química , Adipócitos/metabolismo , Tecido Adiposo/química , Tecido Adiposo Marrom/química , Tecido Adiposo Branco/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal/genética , Peso Corporal/fisiologia , Metabolismo Energético/genética , Expressão Gênica , Hipotálamo/química , Hipotálamo/metabolismo , Leptina/genética , Leptina/metabolismo , Masculino , Desnutrição/genética , Desnutrição/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Obesidade/genética , Obesidade/metabolismo , Fenótipo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Proteínas/genética , Proteínas/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Desmame
7.
Neuroendocrinology ; 90(1): 54-66, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19276635

RESUMO

Numerous data suggest that the development of the sympathoadrenal system is highly sensitive to the perinatal environment. We previously reported that maternal perinatal food restriction by 50% (FR50) altered chromaffin cell (CC) organization and activity in offspring at weaning. This study investigated the effects of FR50 on the postnatal time course of CC functional and structural adaptations. FR50 pups exhibited smaller and more abundant scattered clusters of noradrenergic CCs as early as postnatal day 7 (P7), indicating that morphological changes took place earlier during development. At birth, the adrenaline release was defective in FR50 pups, suggesting that maternal FR50 impaired the non-neurogenic control of catecholamine release. At P4, the catecholamine release in response to insulin-induced hypoglycaemia was also absent in FR50 pups. This was associated with the reduction of adrenal catecholamine contents, indicating that the failure to synthesize catecholamine might lead to impaired secretion. We hypothesized that maternal FR50 accelerated the functional connections between CCs and splanchnic nerve endings, leading to the premature loss of the non-neurogenic response. Acetylcholine-containing synaptic endings seemed more precociously functional in FR50 pups, as suggested by increased levels of acetylcholine esterase activity at P14. At P7, insulin-induced hypoglycaemia caused preferential adrenaline release associated with increased catecholamine contents in both groups. However, the response was accentuated in FR50 pups. At P14, the insulin challenge increased plasma levels of adrenaline in control rats, whereas it markedly enhanced the circulating level of both catecholamines in FR50 pups. We demonstrated that maternal FR50 leads to developmentally impaired noradrenergic CC aggregation and advanced splanchnic neurotransmission maturation associated with altered medulla activity in response to metabolic stress. This might contribute to the long-lasting malprogramming of the adrenal medulla and to the development of chronic adult diseases.


Assuntos
Medula Suprarrenal/crescimento & desenvolvimento , Células Cromafins/fisiologia , Desnutrição , Mães , Efeitos Tardios da Exposição Pré-Natal , Acetilcolinesterase/metabolismo , Medula Suprarrenal/fisiologia , Medula Suprarrenal/fisiopatologia , Animais , Animais Recém-Nascidos , Catecolaminas/sangue , Catecolaminas/metabolismo , Epinefrina/sangue , Epinefrina/metabolismo , Feminino , Hipoglicemia/induzido quimicamente , Hipoglicemia/fisiopatologia , Insulina , Masculino , Norepinefrina/metabolismo , Gravidez , Distribuição Aleatória , Ratos , Ratos Wistar , Estresse Fisiológico/fisiologia , Sinapses/fisiologia
8.
Endocrinology ; 149(2): 470-5, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18006626

RESUMO

A growing body of evidence suggests that maternal undernutrition sensitizes the offspring to the development of energy balance metabolic disorders such as type 2 diabetes, dyslipidemia, and obesity. The present study aimed at examining the impact of maternal undernutrition on leptin plasma levels in newborn male rats and on the arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons that are major leptin targets. Using a model of perinatal maternal 50% food-restricted diet (FR50) in the rat, we evaluated leptin plasma levels and hypothalamic POMC and NPY gene expression from postnatal day (PND) 4 to PND30 in both control and FR50 offspring. In control rats, a postnatal peak of plasma leptin was observed between PND4 and PND14 that reached a maximal value at PND10 (5.17 +/- 0.53 ng/ml), whereas it was dramatically reduced in FR50 pups with the higher concentration at PND7 (0.93 +/- 0.23 ng/ml). In FR50 animals, using semiquantitative RT-PCR and in situ hybridization, we showed that the hypothalamic POMC mRNA level was decreased from PND14 until PND30, whereas NPY gene expression was not significantly modified. In PND21 FR50 animals, we observed strikingly reduced immunoreactive beta-endorphin nerve fibers projecting to the hypothalamic paraventricular nucleus without affecting NPY projections. Our data showed that maternal undernutrition drastically reduces the postnatal surge of plasma leptin, disturbing particularly the hypothalamic wiring as well as the gene expression of the anorexigenic POMC neurons in male rat pups. These alterations might contribute to the adult metabolic disorders resulting from perinatal growth retardation.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Transtornos da Nutrição Fetal/metabolismo , Transtornos da Nutrição Fetal/patologia , Leptina/sangue , Pró-Opiomelanocortina/genética , Fatores Etários , Animais , Animais Recém-Nascidos , Peso Corporal/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Expressão Gênica/fisiologia , Masculino , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Neurônios/metabolismo , Neurônios/patologia , Neurônios/ultraestrutura , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Pró-Opiomelanocortina/metabolismo , Ratos , Ratos Wistar
9.
Psychoneuroendocrinology ; 32 Suppl 1: S16-20, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17644270

RESUMO

Epidemiological and experimental studies have demonstrated that perinatal alterations such as maternal undernutrition are frequently associated with the onset of several chronic adult diseases. Although the physiological mechanisms involved in this "fetal programming" remain largely unknown, it has been shown that early exposure to undernutrition programs hypothalamic-pituitary-adrenal (HPA) axis throughout lifespan. However, the wide spectrum of experimental paradigms used (species, sex, age of the animals, and duration and severity of undernutrition exposure) has given rise to variable results that are difficult to interpret. To circumvent this problem, we used the same experimental protocol of maternal food restriction to study the effects of a severe maternal undernutrition on the HPA axis activity in the male rat offspring throughout the life, namely from fetal stage to adulthood. Mothers exposed to food restriction received 50% (FR50) of the daily intake of pregnant dams during the last week of gestation and lactation. In FR50 fetuses, HPA axis function was reduced and associated with a decreased placental 11beta-HSD2 activity and a greater transplacental transfer of glucocorticoids. At weaning, maternal food restriction reduced HPA axis activity in response to an ether inhalation stress. In young adults (4-month-old), only fine HPA axis alterations were observed, whereas in older ones (8-month-old), maternal undernutrition was associated with chronic hyperactivity of this neuroendocrine axis. Interestingly, excessive glucocorticoids production is observed in a growing number of pathologies such as metabolic, cognitive, immune and inflammatory diseases, suggesting that they could, at least in part, result from fetal undernutrition and thus have a neurodevelopmental origin.


Assuntos
Retardo do Crescimento Fetal/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Desnutrição/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Adaptação Fisiológica , Animais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/etiologia , Masculino , Desnutrição/complicações , Sistemas Neurossecretores/fisiopatologia , Gravidez , Ratos , Índice de Gravidade de Doença , Fatores Sexuais
10.
Mol Metab ; 6(8): 922-930, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28752055

RESUMO

OBJECTIVE: According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates predispose offspring to white adipose tissue (WAT) accumulation. In rodents, adipogenesis mainly develops during lactation. The mechanisms underlying the phenomenon known as developmental programming remain elusive. We previously reported that adult rat offspring from high-fat diet-fed dams (called HF) exhibited hypertrophic adipocyte, hyperleptinemia and increased leptin mRNA levels in a depot-specific manner. We hypothesized that leptin upregulation occurs via epigenetic malprogramming, which takes place early during development of WAT. METHODS: As a first step, we identified in silico two potential enhancers located upstream and downstream of the leptin transcription start site that exhibit strong dynamic epigenomic remodeling during adipocyte differentiation. We then focused on epigenetic modifications (methylation, hydroxymethylation, and histone modifications) of the promoter and the two potential enhancers regulating leptin gene expression in perirenal (pWAT) and inguinal (iWAT) fat pads of HF offspring during lactation (postnatal days 12 (PND12) and 21 (PND21)) and in adulthood. RESULTS: PND12 is an active period for epigenomic remodeling in both deposits especially in the upstream enhancer, consistent with leptin gene induction during adipogenesis. Unlike iWAT, some of these epigenetic marks were still observable in pWAT of weaned HF offspring. Retained marks were only visible in pWAT of 9-month-old HF rats that showed a persistent "expandable" phenotype. CONCLUSIONS: Consistent with the DOHaD hypothesis, persistent epigenetic remodeling occurs at regulatory regions especially within intergenic sequences, linked to higher leptin gene expression in adult HF offspring in a depot-specific manner.


Assuntos
Epigênese Genética , Leptina/genética , Obesidade/genética , Complicações na Gravidez/genética , Tecido Adiposo Branco/metabolismo , Animais , Metilação de DNA , Feminino , Código das Histonas , Leptina/metabolismo , Masculino , Gravidez , Ratos , Ratos Wistar , Regulação para Cima
11.
Endocrinology ; 147(6): 3050-9, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16497807

RESUMO

Epidemiological studies suggest that chronic adult diseases, such as type 2 diabetes and hypertension, can be programmed during fetal and early postnatal life. The nervous system regions governing vegetative functions and the hypothalamic-pituitary-adrenal axis are particularly sensitive to the perinatal nutritional status. Despite recent reports demonstrating that the activity of the sympathoadrenal system can be altered by early life events, the effects of maternal nutrient restriction on the adrenal medulla remain unknown. Using a rat model of maternal perinatal 50% food restriction (FR50) from the second week of gestation until weaning, immunohistochemical experiments revealed alterations in chromaffin cell aggregation and in nerve fiber fasciculation in the adrenal medulla of FR50 pups. These morphological changes were associated with enhanced circulating levels of catecholamines after decapitation (epinephrine by 55% and norepinephrine by 41%). Using macroarrays, we identified several genes whose expression was affected by maternal nutrient restriction. Semiquantitative RT-PCR confirmed the overexpression of four genes involved in neuroendocrine differentiation and neuronal plasticity (chromogranin B, growth-associated protein 43, neurofilament 3, and Slit2) in the adrenal glands of FR50 rats. Using in situ hybridization, we showed that these genes are solely expressed in the adrenal medulla. Together, our results suggest that perinatal maternal undernutrition markedly alters the differentiation of the adrenal medulla during postnatal life, resulting in enhanced activity of chromaffin cells at weaning. These alterations may persist in adulthood and participate to the programming of chronic adult diseases.


Assuntos
Medula Suprarrenal/patologia , Desnutrição/fisiopatologia , Neurônios/patologia , Sistemas Neurossecretores/patologia , Complicações na Gravidez/fisiopatologia , Medula Suprarrenal/crescimento & desenvolvimento , Medula Suprarrenal/metabolismo , Animais , Catecolaminas/análise , Diferenciação Celular , Feminino , Perfilação da Expressão Gênica , Hibridização In Situ , Masculino , Gravidez , Ratos , Ratos Wistar
12.
Psychoneuroendocrinology ; 31(6): 724-35, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16632209

RESUMO

Wistar rats have been selectively bred for high (HABs) or low (LABs) anxiety-related behavior based on results obtained in the elevated-plus maze. They also display robust behavioral differences in a variety of additional anxiety tests. The present study was undertaken to further characterize physiological substrates that contribute to the expression of this anxious trait. We report changes in brain and peripheral structures involved in the regulation of both the hypothalamo-pituitary-adrenal (HPA) and sympatho-adrenal systems. Following exposure to a mild stressor, HABs displayed a hyper-reactivity of the HPA axis associated with a hypo-reactivity of the sympatho-adrenal system and a lower serotonin turnover in the lateral septum and amygdala. At rest, HABs showed a higher adrenal weight and lower tyrosine hydroxylase and phenylethanolamine-N-methyltransferase mRNAs expression in their adrenals than LABs. In the anterior pituitary, HABs also exhibited increased proopiomelanocortin and decreased vasopressin V1b receptor mRNAs expression, whereas glucocorticoid receptor mRNA levels remained unchanged. These results indicate that the behavioral phenotype of HABs is associated with peripheral and central alterations of endocrine mechanisms involved in stress response regulation. Data are discussed in relation to coping strategies adopted to manage stressful situations. In conclusion, HABs can be considered as an useful model to study the etiology and pathophysiology of stress-related disorders and their neuroendocrine substrates.


Assuntos
Glândulas Suprarrenais/metabolismo , Ansiedade/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Adeno-Hipófise/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Glândulas Suprarrenais/inervação , Glândulas Suprarrenais/patologia , Hormônio Adrenocorticotrópico/sangue , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/patologia , Monoaminas Biogênicas/metabolismo , Corticosterona/sangue , Masculino , Sistemas Neurossecretores/metabolismo , Tamanho do Órgão , Feniletanolamina N-Metiltransferase/genética , Feniletanolamina N-Metiltransferase/metabolismo , Adeno-Hipófise/patologia , RNA Mensageiro/análise , Ratos , Ratos Wistar , Septo do Cérebro/metabolismo , Especificidade da Espécie , Sistema Nervoso Simpático/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
14.
J Endocrinol ; 230(1): 39-53, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27122310

RESUMO

According to the Developmental Origin of Health and Disease (DOHaD) concept, alterations of nutrient supply in the fetus or neonate result in long-term programming of individual body weight (BW) setpoint. In particular, maternal obesity, excessive nutrition, and accelerated growth in neonates have been shown to sensitize offspring to obesity. The white adipose tissue may represent a prime target of metabolic programming induced by maternal obesity. In order to unravel the underlying mechanisms, we have developed a rat model of maternal obesity using a high-fat (HF) diet (containing 60% lipids) before and during gestation and lactation. At birth, newborns from obese dams (called HF) were normotrophs. However, HF neonates exhibited a rapid weight gain during lactation, a key period of adipose tissue development in rodents. In males, increased BW at weaning (+30%) persists until 3months of age. Nine-month-old HF male offspring was normoglycemic but showed mild glucose intolerance, hyperinsulinemia, and hypercorticosteronemia. Despite no difference in BW and energy intake, HF adult male offspring was predisposed to fat accumulation showing increased visceral (gonadal and perirenal) depots weights and hyperleptinemia. However, only perirenal adipose tissue depot exhibited marked adipocyte hypertrophy and hyperplasia with elevated lipogenic (i.e. sterol-regulated element binding protein 1 (Srebp1), fatty acid synthase (Fas), and leptin) and diminished adipogenic (i.e. peroxisome proliferator-activated receptor gamma (Pparγ), 11ß-hydroxysteroid dehydrogenase type 1 (11ß-Hds1)) mRNA levels. By contrast, very few metabolic variations were observed in HF female offspring. Thus, maternal obesity and accelerated growth during lactation program offspring for higher adiposity via transcriptional alterations of visceral adipose tissue in a depot- and sex-specific manner.


Assuntos
Tecido Adiposo/metabolismo , Lactação/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Obesidade/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Aumento de Peso/fisiologia , Animais , Peso Corporal , Corticosterona/sangue , Feminino , Intolerância à Glucose/metabolismo , Hiperinsulinismo/metabolismo , Masculino , PPAR gama/genética , PPAR gama/metabolismo , Gravidez , Ratos , Fatores Sexuais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
15.
Diabetes ; 65(3): 554-60, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26631739

RESUMO

The adequate control of glucose homeostasis during both gestation and early postnatal life is crucial for the development of the fetoplacental unit and adaptive physiological responses at birth. Growing evidences indicate that apelin and its receptor, APJ, which are expressed across a wide range of tissues, exert important roles in glucose homeostasis in adults. However, little is known about the function of the apelinergic system during gestation. In this study, we evaluated the activity of this system in rats, the role of apelin in fetal and neonatal glucose homeostasis, and its modulation by maternal food restriction. We found that 1) the apelinergic system was expressed at the fetoplacental interface and in numerous fetal tissues, 2) ex vivo, the placenta released high amounts of apelin in late gestation, 3) intravenous apelin injection in mothers increased the transplacental transport of glucose, and 4) intraperitoneal apelin administration in neonates increased glucose uptake in lung and muscle. Maternal food restriction drastically reduced apelinemia in both mothers and growth-restricted fetuses and altered the expression of the apelinergic system at the fetoplacental interface. Together, our data demonstrate that apelin controls fetal and neonatal glucose homeostasis and is altered by fetal growth restriction induced by maternal undernutrition.


Assuntos
Glicemia/metabolismo , Retardo do Crescimento Fetal/genética , Feto/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Desnutrição/metabolismo , Complicações na Gravidez/metabolismo , Animais , Animais Recém-Nascidos , Apelina , Receptores de Apelina , Glicemia/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Retardo do Crescimento Fetal/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 3/genética , Homeostase/efeitos dos fármacos , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Placenta/metabolismo , Gravidez , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas G/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Neurosci Lett ; 381(3): 211-6, 2005 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-15896472

RESUMO

We have previously shown that prenatal morphine exposure inhibited the hypothalamo-pituitary-adrenal (HPA) axis and altered the hypothalamic metabolism of serotonin during the early postnatal period in the rat and induced a chronic sympathoadrenal hyperactivity under resting conditions in adult male rats. In this study, we examined the effects of prenatal morphine exposure on the responsiveness to an acute ether inhalation stress of the sympathoadrenal and HPA axis and the hippocampal and hypothalamic concentrations of serotonin (5HT) and 5-hydroxylindoleacetic acid (5HIAA) in 3-month-old male rats. The plasma levels of adrenocorticopic hormone (ACTH) and corticosterone (B) did not differ between the two groups both under resting conditions and after ether exposure. Ether inhalation increased adrenal tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNA expression as well as adrenal epinephrine (E) concentration in control rats but not in prenatally morphine-exposed (PM) animals. Under basal conditions, hypothalamic concentrations of 5HT and 5HIAA increased in PM animals. In contrast to control animals, PM rats showed, in response to stress, an increased level of 5HT and 5HIAA in both the hypothalamus and in the hippocampus. In conclusion, prenatal morphine exposure produces long-lasting alterations in brain serotonin transmission and in the sympathoadrenal responsiveness to an acute systemic stress.


Assuntos
Encéfalo/efeitos dos fármacos , Morfina/toxicidade , Entorpecentes/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Serotonina/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Hormônio Adrenocorticotrópico/análise , Animais , Encéfalo/metabolismo , Corticosterona/análise , Éter/farmacologia , Feminino , Ácido Hidroxi-Indolacético/análise , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , RNA Mensageiro , Ratos , Estresse Fisiológico/induzido quimicamente , Sistema Nervoso Simpático/metabolismo
17.
Peptides ; 43: 146-54, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23523777

RESUMO

Epidemiological studies demonstrated that adverse environmental factors leading to intrauterine growth retardation (IUGR) and low birth weight may predispose individuals to increased risk of metabolic syndrome. In rats, we previously demonstrated that adult male IUGR offspring from prenatal 70% food-restricted dams throughout gestation (FR30) were predisposed to energy balance dysfunctions such as impaired glucose intolerance, hyperleptinemia, hyperphagia and adiposity. We investigated whether postweaning moderate high-fat (HF) diet would amplify the phenotype focusing on the hypothalamus gene expression profile. Prenatally undernourished rat offspring were HF-fed from weaning until adulthood while body weight and food intake were measured. Tissue weights, glucose tolerance and plasma endocrine parameters levels were determined in 4-month-old rats. Hypothalamic gene expression profiling of adult FR30 rat was performed using Illumina microarray analysis and the RatRef-12 Expression BeadChip that contains 21,792 rat genes. Under HF diet, contrary to C animals, FR30 rats displayed increased body weight. However, most of the endocrine disorders observed in chow diet-fed adult FR30 were alleviated. We also observed very few gene expression changes in hypothalamus of FR30 rat. Amongst factors involved in hypothalamic energy homeostasis programming system, only the POMC and transthyretin mRNA expression levels were preferentially increased under HF diet. Both elevated gene expression levels may be seen as adaptive mechanisms counteracting against deleterious effects of HF feeding in FR30 animals. This study shows that the POMC gene expression is a key target of long-term developmental programming in prenatally undernourished male rat offspring, specifically within an obesogenic environment.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hipotálamo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/genética , Pró-Opiomelanocortina/genética , Regulação para Cima/genética , Animais , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
18.
PLoS One ; 8(5): e64251, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23691181

RESUMO

Mild gestational hyperglycemia is often associated with fetal overgrowth that can predispose the offspring to metabolic diseases later in life. We hypothesized that unfavorable intrauterine environment may compromise the development of placenta and contribute to fetal overgrowth. Therefore, we developed a rat model and investigated the effects of maternal dysglycemia on fetal growth and placental gene expression. Female rats were treated with single injection of nicotinamide plus streptozotocin (N-STZ) 1-week before mating and were studied at gestational day 21. N-STZ pregnant females displayed impaired glucose tolerance that is associated with a lower insulin secretion. Moderate hyperglycemia induced fetal overgrowth in 40% of newborns, from pregnancies with 10 to 14 pups. The incidence of macrosomia was less than 5% in the N-STZ pregnancies when the litter size exceeds 15 newborns. We found that placental mass and the labyrinthine layer were increased in macrosomic placentas. The expression of genes involved in placental development and nutrient transfer was down regulated in the N-STZ placentas of macrosomic and normosomic pups from pregnancies with 10 to 14 ones. However, we observed that lipoprotein lipase 1 (LPL1) gene expression was significantly increased in the N-STZ placentas of macrosomic pups. In pregnancies with 15 pups or more, the expression of IGFs and glucose transporter genes was also modulated in the control placentas with no additional effect in the N-STZ ones. These data suggest that placental gene expression is modulated by gestational conditions that might disrupt the fetal growth. We described here a new model of maternal glucose intolerance that results in fetal overgrowth. We proposed that over-expression of LPL1 in the placenta may contribute to the increased fetal growth in the N-STZ pregnancies. N-STZ model offers the opportunity to determinate whether these neonatal outcomes may contribute to developmental programming of metabolic diseases in adulthood.


Assuntos
Desenvolvimento Fetal , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hiperglicemia , Placenta/metabolismo , Complicações na Gravidez , Proteínas da Gravidez/metabolismo , Animais , Peso ao Nascer , Feminino , Viabilidade Fetal , Proteínas Facilitadoras de Transporte de Glucose/genética , Lipase Lipoproteica/metabolismo , Tamanho da Ninhada de Vivíparos , Fator de Crescimento Placentário , Gravidez , Proteínas da Gravidez/genética , Ratos , Ratos Wistar
19.
Eur J Pharmacol ; 667(1-3): 13-6, 2011 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-21664905

RESUMO

An association is established between schizophrenia and the development of metabolic alterations including cardiovascular diseases, type 2 diabetes and obesity. Perinatal insults, such as undernutrition, have been shown to increase the propensity to develop these pathologies, reinforcing the idea that schizophrenia may have a neurodevelopmental origin. Moreover, the use of second generation antipsychotics (SGAs) also known as "atypical" neuroleptics has also been demonstrated to exacerbate metabolic anomalies in patients with schizophrenia. SGAs are able to cross the placental barrier and have been detected in milk from women receiving atypical neuroleptics treatment during the perinatal period. To date, the consequences of such treatment have only been examined on the birth weight and the cognitive capacities of the child from women with schizophrenia, but no data is available concerning the putative long-term effects of SGAs on their body weight and metabolic parameters. We have recently reported that rat offspring from prenatally undernourished mothers exhibit a low birth weight associated with modified sensitivity to clozapine and aripiprazole in adulthood reinforcing the idea that some forms of schizophrenia may be acquired during early development. In view of these observations, the risks of perinatal exposure to SGAs must be weighed against the growing evidence that maternal psychiatric illness poses risks to the fetus/newborn as well as for long-term susceptibility to diseases. Thus, metabolic follow-up of children born from mothers treated by SGAs during the perinatal period will be clearly recommended, in particular if they exhibit alterations of their body weight during this early critical period.


Assuntos
Antipsicóticos/efeitos adversos , Exposição Materna/efeitos adversos , Doenças Metabólicas/induzido quimicamente , Assistência Perinatal/métodos , Animais , Antipsicóticos/uso terapêutico , Feminino , Humanos , Doenças Metabólicas/complicações , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico
20.
Eur J Pharmacol ; 667(1-3): 402-9, 2011 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-21514291

RESUMO

Epidemiological and experimental data indicate that maternal undernutrition may sensitize the offspring to the apparition of chronic diseases such as metabolic syndrome and schizophrenia, suggesting that these pathologies may have a developmental origin. To test this hypothesis, we have compared the effects of a 4 weeks treatment of clozapine (30 mg/kg once daily, p.o.) or aripiprazole (10 mg/kg once daily, p.o.) on metabolic and hormonal parameters in 4-month-old male animals from control or 70% prenatally food-restricted mothers (FR30 model). Both neuroleptics did not markedly modify body weight gain and food intake in both controls and FR30 rats. Clozapine decreased insulin secretion in both groups but significantly diminished leptin, corticosterone and glucose plasma levels only in FR30 animals. Aripiprazole decreased corticosterone plasma levels only in FR30 animals. Using quantitative RT-PCR array containing 84 obesity-related genes, we identified several genes involved in energy metabolism regulation whose expression was modified by clozapine or aripiprazole in adult male rat hypothalami. In addition, we demonstrated that expression of some of these genes was differentially affected by each neuroleptic in the hypothalamus of both FR30 and control animals. Although no marked metabolic alterations were observed in both control and FR30 animals after clozapine or aripiprazole treatment, our data indicate that offspring from undernourished mothers exhibit a modified sensitivity to atypical neuroleptics. Our results do not rule out a putative developmental origin of schizophrenia and may help to understand the way by which atypical neuroleptics, such as clozapine, sensitize schizophrenic patients to the development of metabolic disorders.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Desnutrição , Sistema Nervoso/crescimento & desenvolvimento , Piperazinas/farmacologia , Fenômenos Fisiológicos da Nutrição Pré-Natal , Quinolonas/farmacologia , Esquizofrenia/patologia , Animais , Aripiprazol , Peso Corporal/efeitos dos fármacos , Suscetibilidade a Doenças/induzido quimicamente , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/sangue , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Sistema Nervoso/efeitos dos fármacos , Obesidade/genética , Gravidez , Ratos , Ratos Wistar , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia
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