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Prenatal exposure to high-energy diets (HED) increases the susceptibility to behavioral alterations in the male offspring. We addressed whether prenatal HED primes the transgenerational inheritance of structural brain changes impacting anxiety/depression-like behavior in the offspring. For this, we used female Wistar rats exposed to a HED [cafeteria (CAF) diet, n = 6] or chow [control (CON) n = 6] during development. Anxiety and depression-like behavior were evaluated in filial 1 (F1), filial 2 (F2), and filial 3 (F3) male offspring using the open field (OFT), elevated plus maze, novelty suppressed feeding (NSFT), tail suspension (TST), and forced swimming tests. Structural brain changes were identified by deformation-based morphometry (DBM) and diffusion tensor imaging using ex vivo MRI. We found that the F1, F2, and F3 offspring exposed to CAF diet displayed higher anxious scores including longer feeding latency during the NSFT, and in the closed arms, only F1 offspring showed longer stay on edges during the OFT versus control offspring. DBM analysis revealed that CAF offspring exhibited altered volume in the cerebellum, hypothalamus, amygdala, and hippocampus preserved up to the F3 generation of anxious individuals. Also, F3 CAF anxious exhibited greater fractional anisotropy and axial diffusivity (AD) in the amygdala, greater apparent diffusion coefficient in the corpus callosum, and greater AD in the hippocampus with respect to the control. Our results suggest that prenatal and lactation exposure to HED programs the transgenerational inheritance of structural brain changes related to anxiety-like behavior in the male offspring.
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Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Ratos , Animais , Masculino , Feminino , Imagem de Tensor de Difusão , Ratos Wistar , Lactação , Encéfalo/diagnóstico por imagem , Dieta , AnsiedadeRESUMO
Maternal obesity is an important risk factor for obesity, cardiovascular, and metabolic diseases in the offspring. Studies have shown that it leads to hypothalamic inflammation in the progeny, affecting the function of neurons regulating food intake and energy expenditure. In adult mice fed a high-fat diet, one of the hypothalamic abnormalities that contribute to the development of obesity is the damage of the blood-brain barrier (BBB) at the median eminence-arcuate nucleus (ME-ARC) interface; however, how the hypothalamic BBB is affected in the offspring of obese mothers requires further investigation. Here, we used confocal and transmission electron microscopy, transcript expression analysis, glucose tolerance testing, and a cross-fostering intervention to determine the impact of maternal obesity and breastfeeding on BBB integrity at the ME-ARC interface. The offspring of obese mothers were born smaller; conversely, at weaning, they presented larger body mass and glucose intolerance. In addition, maternal obesity-induced structural and functional damage of the offspring's ME-ARC BBB. By a cross-fostering intervention, some of the defects in barrier integrity and metabolism seen during development in an obesogenic diet were recovered. The offspring of obese dams breastfed by lean dams presented a reduction of body mass and glucose intolerance as compared to the offspring continuously exposed to an obesogenic environment during intrauterine and perinatal life; this was accompanied by partial recovery of the anatomical structure of the ME-ARC interface, and by the normalization of transcript expression of genes coding for hypothalamic neurotransmitters involved in energy balance and BBB integrity. Thus, maternal obesity promotes structural and functional damage of the hypothalamic BBB, which is, in part, reverted by lactation by lean mothers.NEW & NOTEWORTHY Maternal dietary habits directly influence offspring health. In this study, we aimed at determining the impact of maternal obesity on BBB integrity. We show that DIO offspring presented a leakier ME-BBB, accompanied by changes in the expression of transcripts encoding for endothelial and tanycytic proteins, as well as of hypothalamic neuropeptides. Breastfeeding in lean dams was sufficient to protect the offspring from ME-BBB disruption, providing a preventive strategy of nutritional intervention during early life.
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Intolerância à Glucose , Obesidade Materna , Humanos , Feminino , Animais , Camundongos , Gravidez , Barreira Hematoencefálica/metabolismo , Eminência Mediana/metabolismo , Obesidade Materna/metabolismo , Mães , Intolerância à Glucose/metabolismo , Obesidade/metabolismo , Hipotálamo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fenômenos Fisiológicos da Nutrição MaternaRESUMO
Introduction: High-fat diet (HFD) consumption is associated with various metabolic disorders and diseases. Both pre-pregnancy and maternal obesity can have long-term consequences on offspring health. Furthermore, consuming an HFD in adulthood significantly increases the risk of obesity and metabolic disorders. However, an intriguing phenomenon known as the obesity paradox suggests that obesity may confer a protective effect on mortality outcomes in sepsis. In sepsis, activation of the cholinergic anti-inflammatory pathway (CAP) can help mitigate systemic inflammation. We employed a metabolic programming model to explore the relationship between maternal HFD consumption and offspring response to sepsis. Methods: We fed female mice either a standard diet (SC) or an HFD during the pre-pregnancy, pregnancy, and lactation periods. Subsequently, we evaluated 28-day-old male offspring. Results: Notably, we discovered that offspring from HFD-fed dams (HFD-O) exhibited a higher survival rate compared with offspring from SC-fed dams (SC-O). Importantly, inhibition of the m1 muscarinic acetylcholine receptor (m1mAChR), involved in the CAP, in the hypothalamus abolished this protection. The expression of m1mAChR in the hypothalamus was higher in HFD-O at different ages, peaking on day 28. Treatment with an m1mAChR agonist could modulate the inflammatory response in peripheral tissues. Specifically, CAP activation was greater in the liver of HFD-O following agonist treatment. Interestingly, lipopolysaccharide (LPS) challenge failed to induce a more inflammatory state in HFD-O, in contrast to SC-O, and agonist treatment had no additional effect. Analysis of spleen immune cells revealed a distinct phenotype in HFD-O, characterized by elevated levels of CD4+ lymphocytes rather than CD8+ lymphocytes. Moreover, basal Il17 messenger RNA (mRNA) levels were lower while Il22 mRNA levels were higher in HFD-O, and we observed the same pattern after LPS challenge. Discussion: Further examination of myeloid cells isolated from bone marrow and allowed to differentiate showed that HFD-O macrophages displayed an anti-inflammatory phenotype. Additionally, treatment with the m1mAChR agonist contributed to reducing inflammatory marker levels in both groups. In summary, our findings demonstrate that HFD-O are protected against LPS-induced sepsis, and this protection is mediated by the central m1mAChR. Moreover, the inflammatory response in the liver, spleen, and bone marrow-differentiated macrophages is diminished. However, more extensive analysis is necessary to elucidate the specific mechanisms by which m1mAChR modulates the immune response during sepsis.
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Doenças Metabólicas , Sepse , Humanos , Gravidez , Feminino , Masculino , Animais , Camundongos , Receptor Muscarínico M1 , Dieta Hiperlipídica/efeitos adversos , Lipopolissacarídeos , Acetilcolina , Obesidade/etiologia , RNA MensageiroRESUMO
[This corrects the article DOI: 10.3389/fcell.2022.893099.].
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Sugar intake has been associated with the development of male reproductive pathologies because of the increase and dysfunction in different adipose tissue depots. The establishment of these dysfunctions in the early stages of development is unknown. We evaluated the effect of maternal (pregnancy and lactation) and male offspring (from weaning to adulthood) consumption of 5% sucrose on perigonadal adipose tissue (PAT) and testis in adulthood. Moreover, two rat groups were compared, both including pregnant and lactating females: Control (C-drinking tap water) and sugar (S-consuming 5% sucrose solution). From weaning to adulthood with male offspring, four subgroups were formed: Control Mother â Control and Sugar offspring (CC, CS) and Sugar Mother â Control and Sugar offspring (SC, SS). At 120 postnatal days, the testes and PAT were collected and morphologically described. Furthermore, we quantified the number and cross-sectional area of perigonadal adipocytes and their distribution. We found that the males from SC and SS groups showed high PAT weight (p < 0.005), a high number (p < 0.05), and a relative frequency of large adipocytes (p < 0.05), establishing these results during gestational and lactation stages, and enhancing in adulthood since postnatal diet and its interaction. More macrophages, mast cells, and Leydig cells were observed in the interstitial space of the testis for the CS, SC, and SS groups, concluding that consumption of a high-carbohydrate maternal diet, program hypertrophy processes in adult PAT, developing and enhancing with sugar consumption during postnatal life. Furthermore, they are associated with inflammatory processes within the interstitial space of the testis.
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The aim of this study was to investigate certain parameters regarding the maternal-fetal outcomes in a diet-induced obesity model. Obese, glucose-intolerant females who were exposed to a high-fat diet prior to pregnancy had lower placental efficiency and lower birth weight pups compared to the controls. Simple linear regression analyses showed that maternal obesity disrupts the proportionality between maternal and fetal outcomes during pregnancy. Maternal obesity is correlated with fetal outcomes, perhaps because of problems with hormonal signaling and exacerbation of inflammation in the maternal metabolic environment. The maternal obese phenotype altered the thickness of the placental layer, the transport of fatty acids, and the expression of growth factors. For example, lower expression of epidermal growth factor receptor (EGFR) mRNA in the obesity-prone group may have contributed to the rupture of the placental layers, leading to adverse fetal outcomes. Furthermore, maintenance of maternal glucose homeostasis and overexpression of placental growth factor (PGF) in the obesity-resistant group likely protected the placenta and fetuses from morphological and functional damage.
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Dieta Hiperlipídica , Obesidade Materna , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Desenvolvimento Fetal , Retardo do Crescimento Fetal/genética , Glucose/metabolismo , Humanos , Camundongos , Obesidade/metabolismo , Fenótipo , Placenta/metabolismo , Fator de Crescimento Placentário/genética , Fator de Crescimento Placentário/metabolismo , GravidezRESUMO
Autism spectrum disorder (ASD) is a disease characterized by reduced social interaction and stereotypic behaviors and related to macroscopic volumetric changes in cerebellar and somatosensory cortices (SPP). Epidemiological and preclinical models have confirmed that a proinflammatory profile during fetal development increases ASD susceptibility after birth. Here, we aimed to globally identify the effect of maternal exposure to high-energy dense diets, which we refer to as cafeteria diet (CAF) on peripheral and central proinflammatory profiles, microglia reactivity, and volumetric brain changes related to assisting defective social interaction in the mice offspring. We found a sex-dependent effect of maternal exposure to CAF diet or inoculation of the dsARN mimetic Poly (I:C) on peripheral proinflammatory and social interaction in the offspring. Notably, maternal exposure to CAF diet impairs social interaction and favors an increase in anxiety in male but not female offspring. Also, CAF diet exposure or Poly (I:C) inoculation during fetal programming promote peripheral proinflammatory profile in the ASD-diagnosed male but not in females. Selectively, we found a robust accumulation of the monocyte chemoattractant protein-1 (MCP-1) in plasma of ASD-diagnosed males exposed to CAF during fetal development. Biological assessment of MCP-1 signaling in brain confirms that systemic injection of MCP-1-neutralizing antibody reestablished social interaction and blocked anxiety, accompanied by a reduction in cerebellar lobule X (CbX) volume and an increase volume of the primary somatosensory (SSP) cortex in male offspring. These data highlight the contribution of diet-dependent MCP-1 signaling on volumetric brain changes and microglia morphology promoting ASD-like behavior in male mice.
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Transtorno do Espectro Autista , Quimiocina CCL2 , Efeitos Tardios da Exposição Pré-Natal , Animais , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Quimiocina CCL2/metabolismo , Feminino , Masculino , Camundongos , Microglia/citologia , Gravidez , Comportamento SocialRESUMO
Maternal obesity increases the risk of nonalcoholic fatty liver disease (NAFLD) in offspring. The Roux-en-Y gastric bypass (RYBG) is effective for achieving weight loss and ameliorates NAFLD. To determine whether these benefits are maintained after pregnancy and/or lactation, and whether they modulate hepatic morphofunction in the next generation, we evaluated hepatic lipid metabolism in Western diet (WD)-obese female rats that underwent RYGB and in their F1 offspring at adulthood. Female Wistar rats consumed a WD from 21 to 130 days of age, before being submitted to RYGB (WD-RYGB-F0) or SHAM (WD-SHAM-F0) operations. After 5 weeks, these females were mated with control male breeders, and the male and female F1 offspring were identified as WD-RYGB-F1 and WD-SHAM-F1. WD-RYGB-F0 dams exhibited lower serum lipids levels, but severe hepatic steatosis and pathological features of advanced liver injury. The hepatic proteins involved in lipogenesis were reduced in WD-RYGB-F0, as were the genes related to ß-oxidation and bile acids (BAs). Although the female and male WD-RYGB-F1 groups did not exhibit hepatic steatosis, the livers of female WD-RYGB-F1 demonstrated higher amounts of lipogenic genes and proteins, while male WD-RYGB-F1 presented a similar downregulation of lipogenic factors to that seen in WD-RYGB-F0 dams. In contrast, maternal and offspring groups of both sexes displayed reductions in the expressions of genes involved in BAs physiology and gluconeogenesis. As such, RYGB aggravates NAFLD after pregnancy and lactation and induces a gender-dependent differential expression of the hepatic lipogenesis pathway in offspring, indicating that female WD-RYGB-F1 may be an increased risk of developing NAFLD.
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Derivação Gástrica , Hepatopatia Gordurosa não Alcoólica , Adulto , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Derivação Gástrica/efeitos adversos , Humanos , Lactação , Lipogênese , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/cirurgia , Gravidez , Ratos , Ratos WistarRESUMO
The first 1,000 days in the life of a human being are a vulnerable stage where early stimuli may program adverse health outcomes in future life. Proper maternal nutrition before and during pregnancy modulates the development of the fetus, a physiological process known as fetal programming. Defective programming promotes non-communicable chronic diseases in the newborn which might be prevented by postnatal interventions such as breastfeeding. Breast milk provides distinct bioactive molecules that contribute to immune maturation, organ development, and healthy microbial gut colonization, and also secures a proper immunological response that protects against infection and inflammation in the newborn. The gut microbiome provides the most critical immune microbial stimulation in the newborn in early life, allowing a well-trained immune system and efficient metabolic settings in healthy subjects. Conversely, negative fetal programming by exposing mothers to diets rich in fat and sugar has profound effects on breast milk composition and alters the immune profiles in the newborn. At this new stage, newborns become vulnerable to immune compromise, favoring susceptibility to defective microbial gut colonization and immune response. This review will focus on the importance of breastfeeding and its immunological biocomponents that allow physiological immune programming in the newborn. We will highlight the importance of immunological settings by breastfeeding, allowing proper microbial gut colonization in the newborn as a window of opportunity to secure effective immunological response.
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The rising rate of childhood overweight follows the increase in maternal obesity, since perinatal events impact offspring in a diversity of metabolic disorders. Despite many studies that have linked dietary consumption, overnutrition, or maternal obesity as the mediators of fetal metabolic programming, there are gaps regarding the knowledge about the contribution of different maternal phenotypes to the development of metabolic disturbances in offspring. This study aimed to investigate whether maternal high-fat diet (HFD) consumption without the development of the obese phenotype would protect offspring from metabolic disturbances. Female mice were fed standard chow diet or a HFD for 4 weeks before mating. HFD females were classified into obesity-resistant (OR) or obesity-prone (OP), according to weight gain. OP females presented with higher adiposity, fasting serum glucose and insulin, cholesterol and non-esterified fatty acid (NEFA). Newborn offspring from OP dams showed higher serum glucose and insulin and alteration in hepatic gene expression that may have contributed to the rise in hepatic fat content and decline of glycogen levels in the liver. Despite offspring from OR and OP females having showed similar growth after the day of delivery, offspring from OP females had higher caloric intake, fasting glucose, serum triglycerides and altered hepatic gene expression, as well as glucose and pyruvate intolerance and lower insulin sensitivity at d28 compared with offspring from OR females. Maternal pre-pregnancy serum glucose, insulin, and NEFA positively correlated with serum glucose and fat liver content and negatively correlated with hepatic glycogen in offspring. In conclusion, our results show that maternal resistance to diet-induced obesity partially protects offspring from early metabolic disturbances.
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Fenômenos Fisiológicos da Nutrição Materna , Obesidade/etiologia , Animais , Dieta Hiperlipídica , Feminino , Masculino , Camundongos , Fatores de ProteçãoRESUMO
Central innate immunity assists time-dependent neurodevelopment by recruiting and interacting with peripheral immune cells. Microglia are the major player of central innate immunity integrating peripheral signals arising from the circumventricular regions lacking the blood-brain barrier (BBB), via neural afferent pathways such as the vagal nerve and also by choroid plexus into the brain ventricles. Defective and/or unrestrained activation of central and peripheral immunity during embryonic development might set an aberrant connectome establishment and brain function, leading to major psychiatric disorders in postnatal stages. Molecular candidates leading to central and peripheral innate immune overactivation identified metabolic substrates and lipid species as major contributors of immunological priming, supporting the role of a metabolic flexibility node during trained immunity. Mechanistically, trained immunity is established by an epigenetic program including DNA methylation and histone acetylation, as the major molecular epigenetic signatures to set immune phenotypes. By definition, immunological training sets reprogramming of innate immune cells, enhancing or repressing immune responses towards a second challenge which potentially might contribute to neurodevelopment disorders. Notably, the innate immune training might be set during pregnancy by maternal immune activation stimuli. In this review, we integrate the most valuable scientific evidence supporting the role of metabolic cues assisting metabolic flexibility, leading to innate immune training during development and its effects on aberrant neurological phenotypes in the offspring. We also add reports supporting the role of methylation and histone acetylation signatures as a major epigenetic mechanism regulating immune training.
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Imunidade Inata , Metabolismo , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/imunologia , Animais , Epigênese Genética , Humanos , Imunidade Inata/genética , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Lipídeos/química , Metabolismo/genéticaRESUMO
AIM: The aim of this study was to evaluate the effects of maternal exposure to a high-fat diet associated with neonatal administration of kaempferol on somatic growth, biochemical profile and feeding behavior in offspring. MATERIALS AND METHODS: Wistar rats were distributed according to diet during pregnancy and lactation into Control (C; 3.4 kcal/g; 12% kcal/lipids) or High-fat (HFD; 4.6 kcal/g; 51% kcal/lipids) groups. In the offspring, vehicle (V) or kaempferol (K, 1 mg/kg) were administered from the 8th until the 21st postnatal day (PND). Maternal body weight (BW), caloric intake and adiposity were measured. In the offspring, somatic growth parameters were evaluated on the 7th, 14th, 21st, 25th and 30th PND, except for BW, which was measured from the 8th to the 21st and from the 25th to the 30th PND. Feeding behavior was assessed by food intake and behavioral satiety sequence (BSS) on the 30th PND. The biochemical profile and relative weight of adipose tissue of offspring were also measured. KEY FINDINGS: Dams exposed to HFD showed no difference in body weight and caloric intake but exhibited increased adiposity. Neonatal administration of kaempferol increased body weight after weaning and somatic growth in the offspring of HFD dams. Neonatal kaempferol also reduced adiposity and serum creatinine levels in offspring. Neither maternal diet nor kaempferol altered offspring feeding behavior. SIGNIFICANCE: Neonatal administration of kaempferol promotes increased somatic growth post-weaning, reduces adiposity, and does not alter feeding behavior in offspring from high-fat dams.
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Adiposidade/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Quempferóis/farmacologia , Tecido Adiposo , Animais , Animais Recém-Nascidos/metabolismo , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Ingestão de Energia/efeitos dos fármacos , Feminino , Quempferóis/metabolismo , Lactação/efeitos dos fármacos , Masculino , Exposição Materna/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/tratamento farmacológico , Gravidez , Ratos , Ratos Wistar , DesmameRESUMO
Maternal nutritional programming by a high-fat (HF) diet is related to hepatic lipid accumulation and steatosis in offspring. Conjugated linoleic acid (CLA) might ameliorate impaired hepatic lipid homoeostasis; therefore, the aim was to investigate the potential preventive effect of maternal CLA consumption on TAG metabolism alterations induced by HF diets in adult male rat offspring receiving or not receiving CLA. Female Wistar rats were fed a control (C) diet, HF diet or HF diet supplemented with CLA (HF+CLA) for 4 weeks before mating and throughout pregnancy and lactation. After weaning, for 9 weeks, male offspring of C or HF rats continued with the same diets as their mothers (C/C or HF/HF groups, respectively) and male offspring of HF+CLA rats were fed HF or HF+CLA diets (HF+CLA/HF or HF+CLA/HF+CLA groups, respectively). Nutritional parameters, serum and liver TAG levels, the TAG secretion rate (TAG-SR) and the activities as well as gene expression of key hepatic enzymes involved in TAG regulation were assessed. The most interesting results were that maternal CLA decreased epididymal white adipose tissue weight and prevented serum and liver TAG accumulation induced by a HF diet in adult male offspring receiving or not receiving CLA. The prevention of liver steatosis in HF+CLA/HF+CLA and HF+CLA/HF offspring was associated with an increased hepatic TAG-SR. Overall, this study provides evidence that maternal CLA consumption programmes TAG regulation and in this way contributes to lowering lipid levels in tissues and preventing liver steatosis in particular.
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Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Fígado Gorduroso/prevenção & controle , Ácidos Linoleicos Conjugados/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Tecido Adiposo Branco/metabolismo , Animais , Fígado Gorduroso/etiologia , Feminino , Fígado/metabolismo , Masculino , Exposição Materna/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos WistarRESUMO
OBJECTIVES: The aim of this study was to observe the developmental origins of health and disease affecting offspring owing to the consumption of a diet containing high fructose by the father or mother or both, considering that progeny only received a control diet during postnatal life. METHODS: Male (future father) and female (future mother) C57 BL/6 mice were fed a high-fructose diet (HFru; 45% energy) or a control diet (C) for 8 wk before mating until lactation. The offspring was termed according to sex, maternal diet (first acrostic), and paternal diet (second acrostic); and received a balanced control diet until 3-mo of age when they were sacrificed. Body mass (BM), plasmatic leptin, adiponectin, uric acid, and systolic blood pressure (BP) were measured in mature offspring. RESULTS: Fasting glycemia and insulin were elevated in HFru fathers and mothers. Although there was no change in BM, fasting glycemia, or insulin of the offspring, those of HFru fathers, HFru mothers, and HFru fathers and mothers presented higher genital fat pad, leptin, uric acid, and BP, and lower adiponectin. The values of leptin and BP were maximized when both parents consumed a HFru diet. Also, there was sexual dimorphism in most of the variables, with the male offspring being affected to a greater extent than the females. CONCLUSIONS: Consumption of a fructose-rich diet by the father, the mother, or both negatively affected the adipokines, BP, and uric acid concentrations of mature offspring, with males being more affected than females. It is significant to consider that high BP and plasmatic uric acid correspond to markers of elevated cardiovascular risk in the progeny.
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Fenômenos Fisiológicos da Nutrição Animal , Açúcares da Dieta/efeitos adversos , Frutose/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores Sexuais , Adiponectina/sangue , Tecido Adiposo/fisiopatologia , Animais , Glicemia/análise , Pressão Sanguínea , Pai , Comportamento Alimentar , Feminino , Fatores de Risco de Doenças Cardíacas , Insulina/sangue , Leptina/sangue , Masculino , Exposição Materna , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Camundongos Endogâmicos C57BL , Mães , Exposição Paterna , Gravidez , Ácido Úrico/sangueRESUMO
PURPOSE: Obesity is predominant in women of reproductive age. Roux-en-Y gastric bypass (RYGB) is the most common bariatric procedure that is performed in obese women for weight loss and metabolic improvement. However, some studies suggest that this procedure negatively affects offspring. Herein, using Western diet (WD)-obese female rats, we investigated the effects of maternal RYGB on postnatal body development, glucose tolerance, insulin secretion and action in their adult male F1 offspring. METHODS: Female Wistar rats consumed a Western diet (WD) for 18 weeks, before being submitted to RYGB (WD-RYGB) or SHAM (WD-SHAM) operations. After 5 weeks, WD-RYGB and WD-SHAM females were mated with control male breeders, and the F1 offspring were identified as: WD-RYGB-F1 and WD-SHAM-F1. RESULTS: The male F1 offspring of WD-RYGB dams exhibited decreased BW, but enhanced total nasoanal length gain. At 120 days of age, WD-RYGB-F1 rats displayed normal fasting glycemia and glucose tolerance but demonstrated reduced insulinemia and higher glucose disappearance after insulin stimulus. In addition, these rodents presented insulin resistance in the gastrocnemius muscle and retroperitoneal fat, as judged by lower Akt phosphorylation after insulin administration, but an increase in this protein in the liver. Finally, the islets from WD-RYGB-F1 rats secreted less insulin in response to glucose and displayed increased ß-cell area and mass. CONCLUSIONS: RYGB in WD dams negatively affected their F1 offspring, leading to catch-up growth, insulin resistance in skeletal muscle and white fat, and ß-cell dysfunction. Therefore, our data are the first to demonstrate that the RYGB in female rats may aggravate the metabolic imprinting induced by maternal WD consumption, in their male F1 descendants. However, since we only used male F1 rats, further studies are necessary to demonstrate if such effect may also occur in female F1 offspring from dams that underwent RYGB operation.
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Glicemia , Peso Corporal , Derivação Gástrica/efeitos adversos , Insulina/sangue , Pâncreas/metabolismo , Pâncreas/fisiopatologia , Animais , Feminino , Masculino , Mães , Obesidade/cirurgia , Ratos , Ratos WistarRESUMO
Autism spectrum disorder (ASD) is a complex neurodevelopmental disease which involves functional and structural defects in selective central nervous system (CNS) regions harming capability to process and respond to external stimuli. In addition to genetic background, etiological causes of ASD have not been fully clarified. Maternal immune activation (MIA) during pregnancy have been proposed as a potential etiological cause leading to aberrant synaptic pruning and microglia-mediated neurogenesis impairment. Several clinical studies suggest that pro-inflammatory profile during maternal obesity associates with a higher risk of having a child with autism. In this context, the effect of maternal programing by high fat diet overconsumption during pregnancy sets a pro-inflammatory profile partly dependent on an epigenetic program of immunity which promotes brain micro and macrostructural abnormalities in the offspring that might last through adulthood accompanied by phenotypic changes in ASD subjects. Of note, maternal programming of inflammation during development seems to integrate the CNS and peripheral immune system cross-talk which arrays central inflammatory domains coordinating ASD behavior. In this review, we discuss basic and clinical studies regarding the effects of obesity-induced MIA on peripheral immune cells and microglia priming and their relationship with brain structural alterations in ASD models. Also, we show supportive evidence stating the role of maternal programming on epigenetic gene activation in immune cells of ASD subjects. We suggest that maternal programming by hypercaloric diets during development sets a central and peripheral immune cross-talk which potentially might modulate brain macro and microstructural defects leading to autism susceptibility.
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Transtorno do Espectro Autista/metabolismo , Dieta Hiperlipídica/efeitos adversos , Suscetibilidade a Doenças/metabolismo , Mediadores da Inflamação/metabolismo , Hipernutrição/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/imunologia , Suscetibilidade a Doenças/induzido quimicamente , Suscetibilidade a Doenças/imunologia , Epigênese Genética/fisiologia , Feminino , Humanos , Mediadores da Inflamação/imunologia , Saúde Materna , Obesidade/complicações , Obesidade/imunologia , Obesidade/metabolismo , Hipernutrição/complicações , Hipernutrição/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologiaRESUMO
Conjugated linoleic acid (CLA) might regulate the lipid depots in liver and adipose tissue. As there is an association between maternal nutrition, fat depots and risk of offspring chronic disease, the aim was to investigate the effect of maternal CLA consumption on TAG regulation and some inflammatory parameters in adult male rat offspring receiving or not receiving CLA. Female Wistar rats were fed control (C) or CLA-supplemented (1 %, w/w) diets during 4 weeks before and throughout pregnancy and lactation. After weaning, male offspring of CLA rats were fed C or CLA diets (CLA/C and CLA/CLA groups, respectively), whereas C male rat offspring were fed a C diet (C/C group) for 9 weeks. Serum TAG levels were increased in the CLA/CLA and CLA/C groups, associated with a reduction of lipoprotein lipase activity and weights of adipose tissue. The liver TAG levels were decreased in the CLA/CLA group, related to a significant reduction of fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC) and glucose-6-phosphate dehydrogenase enzyme activities, as well as to the mRNA levels of FAS, ACC, stearoyl-CoA desaturase-1 and sterol regulatory element-binding protein-1c. Even though normal TAG levels were found in the liver of CLA/C rats, a reduction of lipogenesis was also observed. Thus, these results demonstrated a programming effect of CLA on the lipid metabolic pathways leading to a preventive effect on the TAG accretion in adipose tissue and the liver of male rat offspring. This knowledge could be important to develop some dietary strategies leading to a reduced incidence of obesity and fatty acid liver disease in humans.