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Maternal high-fat diet intake has profound effects on the long-term health of offspring, predisposing them to a higher susceptibility to obesity and metabolic dysfunction-associated steatotic liver disease. However, the detailed mechanisms underlying the role of a maternal high-fat diet in hepatic lipid accumulation in offspring, especially at the weaning age, remain largely unclear. In this study, female C57BL/6J mice were randomly assigned to either a high-fat diet or a control diet, and lipid metabolism parameters were assessed in male offspring at weaning. Gut microbiota analysis and targeted metabolomics of short-chain fatty acids (SCFAs) in these offspring were further performed. Both in vivo and in vitro studies were conducted to explore the role of butyrate in hepatic cholesterol excretion in the liver and HepG2 cells. Our results showed that maternal high-fat feeding led to obesity and dyslipidemia, and exacerbated hepatic lipid accumulation in the livers of offspring at weaning. We observed significant decreases in the abundance of the Firmicutes phylum and the Allobaculum genus, known as producers of SCFAs, particularly butyrate, in the offspring of dams fed a high-fat diet. Additionally, maternal high-fat diet feeding markedly decreased serum butyrate levels and down-regulated ATP-binding cassette transporters G5 (ABCG5) in the liver, accompanied by decreased phosphorylated AMP-activated protein kinase (AMPK) and histone deacetylase 5 (HADC5) expressions. Subsequent in vitro studies revealed that butyrate could induce ABCG5 activation and alleviate lipid accumulation via the AMPK-pHDAC5 pathway in HepG2 cells. Moreover, knockdown of HDAC5 up-regulated ABCG5 expression and promoted cholesterol excretion in HepG2 cells. In conclusion, our study provides novel insights into how maternal high-fat diet feeding inhibits hepatic cholesterol excretion and down-regulates ABCG5 through the butyrate-AMPK-pHDAC5 pathway in offspring at weaning.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5 , Butiratos , Colesterol , Dieta Alta en Grasa , Microbioma Gastrointestinal , Hígado , Ratones Endogámicos C57BL , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Butiratos/metabolismo , Humanos , Hígado/metabolismo , Células Hep G2 , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Masculino , Colesterol/metabolismo , Colesterol/sangre , Embarazo , Ratones , Metabolismo de los Lípidos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , Obesidad/metabolismo , Obesidad/microbiología , Dislipidemias/metabolismo , Dislipidemias/microbiología , Dislipidemias/etiología , LipoproteínasRESUMEN
BACKGROUND: Pediatric low-grade glioma incidence has been rising in the U.S., mirroring the rising rates of pediatric and maternal obesity. Recently, children of obese mothers were demonstrated to develop brain tumors at higher rates. Importantly, obesity in the U.S. is largely driven by diet, given the prevalence of high fat and high sugar (HFHS) food choices. Since high-fat diet exposure can increase embryonic neuroglial progenitor cell (NPC) proliferation, the potential cells of origin for low-grade glioma, we hypothesized that in utero exposure to an obesogenic diet would modify pediatric brain penetrance and latency by affecting the tumor cell of origin. METHODS: We employed several murine models of the Neurofibromatosis type 1 (NF1) pediatric brain tumor predisposition syndrome, in which optic pathway gliomas (Nf1-OPGs) arise from NPCs in the embryonic third ventricular zone (TVZ). We exposed dams and offspring to an obesogenic HFHS diet or control chow and analysed fetal neurodevelopment at E19.5 and tumor formation at 6w-3mo. RESULTS: Progeny from HFHS diet-exposed dams demonstrated increased TVZ NPC proliferation and glial differentiation. Dietary switch cohorts confirmed that these effects were dependent upon maternal diet, rather than maternal weight. Obesogenic diet (Ob) similarly accelerated glioma formation in a high-penetrance Nf1-OPG strain and increased glioma penetrance in two low-penetrance Nf1-OPG strains. In contrast, Ob exposure in the postnatal period alone did not recapitulate these effects. CONCLUSIONS: These findings establish maternal obesogenic diet as a risk factor for murine Nf1-OPG formation, acting in part through in utero effects on the tumor cell of origin.
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PURPOSE: Maternal high-fat diet (HF) programs obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), hypertriglyceridemia, and hyperglycemia associated with increased endocannabinoid system (ECS) in the liver of adult male rat offspring. We hypothesized that maternal HF would induce sex specific ECS changes in the liver of newborn rats, prior to obesity onset, and maternal fish oil (FO) supplementation would reprogram the ECS and lipid metabolism markers preventing liver triglycerides (TG) accumulation. METHODS: Female rats received a control (CT) (10.9% fat) or HF (28.7% fat) diet 8 weeks prior to mating and during pregnancy. A subgroup of HF dams received 3% FO supplementation in the HF diet (35.4% fat) during pregnancy (HFFO). Serum hormones and liver TG, ECS, lipid metabolism, oxidative stress and autophagy markers were assessed in male and female newborn offspring. RESULTS: Maternal HF diet increased liver cannabinoid receptor 1 (CB1) in males and decreased CB2 in females, with no effect on liver TG. Maternal FO supplementation reduced liver CB1 regardless of the offspring sex, but reduced TG liver content only in females. FO reduced the liver content of the endocannabinoid anandamide in males, and the content of 2-arachidonoylglycerol in both sexes. Maternal HF increased lipogenic and decreased lipid oxidation markers, and FO induced the opposite regulation in the liver of offspring. CONCLUSION: Prenatal HF and FO differentially modulate liver ECS in the offspring before obesity and MASLD development. These results suggest that maternal nutrition at critical stages of development can modulate the offspring's ECS, predisposing or preventing the onset of metabolic diseases.
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Animales Recién Nacidos , Dieta Alta en Grasa , Suplementos Dietéticos , Endocannabinoides , Aceites de Pescado , Lipogénesis , Hígado , Fenómenos Fisiologicos Nutricionales Maternos , Animales , Femenino , Embarazo , Aceites de Pescado/farmacología , Aceites de Pescado/administración & dosificación , Endocannabinoides/metabolismo , Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Hígado/efectos de los fármacos , Ratas , Masculino , Lipogénesis/efectos de los fármacos , Biomarcadores/sangre , Biomarcadores/metabolismo , Ratas Wistar , Efectos Tardíos de la Exposición Prenatal , Metabolismo de los Lípidos/efectos de los fármacos , Triglicéridos/sangreRESUMEN
Early-life exposure to high-fat diets (HF) can program metabolic and cognitive alterations in adult offspring. Although the hippocampus plays a crucial role in memory and metabolic homeostasis, few studies have reported the impact of maternal HF on this structure. We assessed the effects of maternal HF during lactation on physiological, metabolic, and cognitive parameters in young adult offspring mice. To identify early-programming mechanisms in the hippocampus, we developed a multi-omics strategy in male and female offspring. Maternal HF induced a transient increased body weight at weaning, and a mild glucose intolerance only in 3-month-old male mice with no change in plasma metabolic parameters in adult male and female offspring. Behavioral alterations revealed by a Barnes maze test were observed both in 6-month-old male and female mice. The multi-omics strategy unveiled sex-specific transcriptomic and proteomic modifications in the hippocampus of adult offspring. These studies that were confirmed by regulon analysis show that, although genes whose expression was modified by maternal HF were different between sexes, the main pathways affected were similar with mitochondria and synapses as main hippocampal targets of maternal HF. The effects of maternal HF reported here may help to better characterize sex-dependent molecular pathways involved in cognitive disorders and neurodegenerative diseases.
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Dieta Alta en Grasa , Efectos Tardíos de la Exposición Prenatal , Animales , Ratones , Femenino , Masculino , Humanos , Dieta Alta en Grasa/efectos adversos , Obesidad/etiología , Obesidad/metabolismo , Multiómica , Proteómica , Lactancia , Hipocampo/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Efectos Tardíos de la Exposición Prenatal/metabolismoRESUMEN
Early life nutrition can reprogram development and exert long-term consequences on body weight regulation. In mice, maternal high-fat diet (HFD) during lactation predisposed male but not female offspring to diet-induced obesity when adult. Molecular and cellular changes in the hypothalamus at important time points are examined in the early postnatal life in relation to maternal diet and demonstrated sex-differential hypothalamic reprogramming. Maternal HFD in lactation decreased the neurotropic development of neurons formed at the embryo stage (e12.5) and impaired early postnatal neurogenesis in the hypothalamic regions of both males and females. Males show a larger increased ratio of Neuropeptide Y (NPY) to Pro-opiomelanocortin (POMC) neurons in early postnatal neurogenesis, in response to maternal HFD, setting an obese tone for male offspring. These data provide insights into the mechanisms by which hypothalamic reprograming by early life overnutrition contributes to the sex-dependent susceptibility to obesity in adult life in mice.
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Dieta Alta en Grasa , Obesidad , Femenino , Ratones , Animales , Masculino , Dieta Alta en Grasa/efectos adversos , Obesidad/etiología , Hipotálamo , Peso Corporal , LactanciaRESUMEN
Prenatal high-fat diet (HFD) or exposure to microplastics can affect the accumulation of liver fat in offspring. We sought to determine the effects of maternal HFD intake and microplastic exposure on fatty liver injury through oxidative stress in pups. Pregnant female Sprague-Dawley rats were randomly divided into maternal HFD (experimental group) or normal control diet (NCD; control group) groups with or without microplastic exposure. As a result, the following groups were established: HFD-L (HFD + microplastics, 5 µm, 100 µg/L), HFD-H (HFD + microplastics, 5 µm, 1000 µg/L), NCD-L (NCD + microplastics, 5 µm, 100 µg/L), and NCD-H (NCD + microplastics, 5 µm, 1000 µg/L). The pups were sacrificed on postnatal day 7 (PD7). Liver histology revealed increased hepatic lipid accumulation in pups in the HFD-L and HFD-H groups compared to those in the HFD, NCD-L, NCD-H, and NCD groups on PD7. Similarly, liver TUNEL staining and cellular apoptosis were found to increase in pups in the HFD-L and HFD-H groups compared to those in the HFD, NCD-L, NCD-H, and NCD groups. The expression levels of malondialdehyde, a lipid peroxidation marker, were high in the HFD, HFD-L, and HFD-H groups; however, the highest expression was observed in the HFD-H group (p < 0.05). The levels of glutathione peroxidase, an antioxidant enzyme, decreased in the HFD, HFD-L, and HFD-H groups (p < 0.05). Overall, oxidative stress with cellular apoptosis plays a vital role in liver injury in offspring after maternal intake of HFD and exposure to microplastic; such findings may shed light on future therapeutic strategies.
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Dieta Alta en Grasa , Enfermedades no Transmisibles , Femenino , Masculino , Ratas , Embarazo , Animales , Ratas Sprague-Dawley , Dieta Alta en Grasa/efectos adversos , Microplásticos , Plásticos , Hígado , Estrés Oxidativo , VitaminasRESUMEN
The environment encountered by the fetus during its development exerts a profound influence on its physiological function and disease risk in adulthood. Women's intake of high-fat diet during pregnancy and lactation has gradually become an issue of widespread concern. Maternal high-fat diet will not only cause abnormal neurological development and metabolic syndrome symptoms in the offspring, but also affect the fertility of female offspring. Maternal high-fat diet affects the expression of genes related to follicle growth in offspring, such as AAT, AFP and GDF-9, which reduces the number of follicles and impairs follicle development. Additionally, maternal high-fat diet also affects ovarian health by inducing ovarian oxidative stress and cell apoptosis, which collectively can impair the reproductive potential of female offspring. Reproductive potential carries significant importance for both humans and animals. Therefore, this review aims to describe the effect of maternal exposure to high-fat diet on the ovarian development of offspring and to discuss possible mechanisms by which maternal diet affects the growth and metabolism of offspring.
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Dieta Alta en Grasa , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Animales , Humanos , Dieta Alta en Grasa/efectos adversos , Efectos Tardíos de la Exposición Prenatal/veterinaria , Reproducción , Ovario/metabolismo , Folículo Ovárico , Lactancia/fisiología , Fenómenos Fisiologicos Nutricionales Maternos/fisiologíaRESUMEN
BACKGROUND: The developmental biology for the nonalcoholic fatty liver disease and coronary heart disease are known but elaborative ideas of triglycerides phenomenon in the embryo-genesis of the liver and the heart are still not clear. OBJECTIVE: The aim of the study was to relate different triglycerides like LXRα, LPL, LDL R, PPARG-, and SREBP-1C expression in the high fat-fed mice with the normal-fed diet mice in the process of developmen-tal and embryo-genesis biology. METHODS: Tissue preparation was done by RIPA lysis. Different protein content was obtained via western blot for the 6 samples namely A.3 months embryo B.4 months embryo C.Birth day embryo D.3 days infant E. 2 weeks infant F. 4 weeks infant. Protein lysates from the heart tissues of the mice were obtained via ho-mogenization and centrifugation. Hematoxylin and Eosin staining (H and E) were done to see the fat droplets in the liver tissues at the different developmental stages. RESULT: LXRα,SREBP-1C expression in 3 months embryo and 4 months embryo is highly expressed in the high-fat diet. LDL-R in the high-fat diet mice is increased in 3 days infant heart but in 3 months and 4 months embryo it has low expression but from the 0th day to the 4 weeks the expression is in a decreasing trend. Similarly, LPL is highly expressed in 3 months embryo and 0th day(Birthday) and thus low expression indecreasing order until 4 weeks infant. Thus, these results collectively show that a maternal HF diet in-creases the expression of proteins such as LPL, and LDLr in the embryo phase and thus getting normal ex-pressions in the adult phase that facilitate Triglycerides (TAG) hydrolysis across the liver and the heart. Also, maternal high-fat diet increases the SREBP1c expression, leading to stimulation of LPL Expression. CONCLUSION: In summary, using a pregnant mice model, we found that a maternal high-fat diet increases fe-tal fat accumulation. Elevated placental LPL activity and expression of genes that facilitate placental lipid transport suggest that enhanced placental lipid transport may play a key role in maternal nutrition and obesi-ty-induced fetal fat accumulation.
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SCOPE: Circadian rhythms profoundly impact metabolism and the gut microbiota. A maternal high-fat diet (HFD) exerts effects on the metabolic syndrome of adult offspring in a sex-specific manner, the underlying mechanisms, however, remain unclear. METHODS AND RESULTS: Female mice are fed an HFD and raise their offspring on a standard chow diet until 24 weeks. The glucose tolerance, insulin sensitivity, and diurnal rhythms of serum metabolic profiles are assessed in male and female adult offspring. Simultaneously, 16S rRNA is applied to characterize gut microbiota diurnal rhythms. The study finds that maternal HFD tends to deteriorate glucose tolerance and impairs insulin sensitivity in male offspring, but not female offspring, which can be associated with the circadian alterations of serum metabolic profiles in male offspring. As expected, maternal HFD sex-specifically alters diurnal rhythms of the gut microbiota, which exhibits putative associations with metabolic profiles in males. CONCLUSIONS: The present study identifies the critical role of gut microbiota diurnal rhythms in triggering sex-biased metabolic diurnal rhythms in response to maternal HFD, at least in part. As early life may be a critical window for preventing metabolic diseases, these findings provide the basis for developing chronobiology applications targeting the gut microbiota to combat early metabolic alterations, especially in males.
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Microbioma Gastrointestinal , Resistencia a la Insulina , Femenino , Ratones , Masculino , Animales , Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina/fisiología , Microbioma Gastrointestinal/fisiología , ARN Ribosómico 16S , Glucosa , Ratones Endogámicos C57BLRESUMEN
Introduction: Maternal high-fat (HF) diet during gestation and lactation programs obesity in rat offspring associated with sex-dependent and tissue-specific changes of the endocannabinoid system (ECS). The ECS activation induces food intake and preference for fat as well as lipogenesis. We hypothesized that maternal HF diet would increase the lipid endocannabinoid levels in breast milk programming cannabinoid and dopamine signaling and food preference in rat offspring. Methods: Female Wistar rats were assigned into two experimental groups: control group (C), which received a standard diet (10% fat), or HF group, which received a high-fat diet (29% fat) for 8 weeks before mating and during gestation and lactation. Milk samples were collected to measure endocannabinoids and fatty acids by mass spectrometry. Cannabinoid and dopamine signaling were evaluated in the nucleus accumbens (NAc) of male and female weanling offspring. C and HF offspring received C diet after weaning and food preference was assessed in adolescence. Results: Maternal HF diet reduced the milk content of anandamide (AEA) (p<0.05) and 2-arachidonoylglycerol (2-AG) (p<0.05). In parallel, maternal HF diet increased adiposity in male (p<0.05) and female offspring (p<0.05) at weaning. Maternal HF diet increased cannabinoid and dopamine signaling in the NAc only in male offspring (p<0.05), which was associated with higher preference for fat in adolescence (p<0.05). Conclusion: Contrary to our hypothesis, maternal HF diet reduced AEA and 2-AG in breast milk. We speculate that decreased endocannabinoid exposure during lactation may induce sex-dependent adaptive changes of the cannabinoid-dopamine crosstalk signaling in the developing NAc, contributing to alterations in neurodevelopment and programming of preference for fat in adolescent male offspring.
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Cannabinoides , Endocannabinoides , Ratas , Animales , Masculino , Femenino , Dieta Alta en Grasa/efectos adversos , Leche , Dopamina , Preferencias Alimentarias , Ratas Wistar , ObesidadRESUMEN
Maternal obesity programs the risk for development of nonalcoholic fatty liver disease (NAFLD) in offspring. Maternal exercise is a potential intervention to prevent developmentally programmed phenotypes. We hypothesized that maternal exercise would protect from progression of NAFLD in offspring previously exposed to a maternal obesogenic diet. Female mice were fed chow (CON) or high fat, fructose, cholesterol (HFFC) and bred with lean males. A subset had an exercise wheel introduced 4 weeks after starting the diet to allow for voluntary exercise. The offspring were weaned to the HFFC diet for 7 weeks to induce NAFLD. Serum, adipose, and liver tissue were collected for metabolic, histologic, and gene expression analyses. Cecal contents were collected for 16S sequencing. Global metabolomics was performed on liver. Female mice fed the HFFC diet had increased body weight prior to adding an exercise wheel. Female mice fed the HFFC diet had an increase in exercise distance relative to CON during the preconception period. Exercise distance was similar between groups during pregnancy and lactation. CON-active and HFFC-active offspring exhibited decreased inflammation compared with offspring from sedentary dams. Fibrosis increased in offspring from HFFC-sedentary dams compared with CON-sedentary. Offspring from exercised HFFC dams exhibited less fibrosis than offspring from sedentary HFFC dams. While maternal diet significantly affected the microbiome of offspring, the effect of maternal exercise was minimal. Metabolomics analysis revealed shifts in multiple metabolites including several involved in bile acid, 1-carbon, histidine, and acylcarnitine metabolism. This study provides preclinical evidence that maternal exercise is a potential approach to prevent developmentally programmed liver disease progression in offspring.
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Enfermedad del Hígado Graso no Alcohólico , Efectos Tardíos de la Exposición Prenatal , Humanos , Femenino , Masculino , Ratones , Embarazo , Animales , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/patología , Dieta , Obesidad/etiología , Obesidad/prevención & control , Obesidad/metabolismo , Hígado/metabolismo , Colesterol , Fibrosis , Dieta Alta en Grasa/efectos adversos , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal/metabolismoRESUMEN
Advanced maternal age and obesity are the main risk factors to develop gestational diabetes mellitus (GDM). Obesity is a consequence of the increased storage of triacylglycerol (TG). Cytosolic and lysosomal lipid hydrolases break down TG and cholesteryl esters (CE) to release fatty acids (FA), free cholesterol, and glycerol. We have recently shown that intracellular lipases are present and active in the mouse placenta and that deficiency of lysosomal acid lipase alters placental and fetal lipid homeostasis. To date, intracellular lipid hydrolysis in GDM has been poorly studied despite the important role of FA in this condition. Therefore, we hypothesized that intracellular lipases are dysregulated in pregnancies complicated by maternal high-fat/high-cholesterol (HF/HCD) feeding with and without GDM. Placentae of HF/HCD-fed mice with and without GDM were more efficient, indicating increased nutrient transfer to the fetus. The increased activity of placental CE but not TG hydrolases in placentae of dams fed HF/HCD with or without GDM resulted in upregulated cholesterol export to the fetus and placental TG accumulation. Our results indicate that HF/HCD-induced dysregulation of placental lipid hydrolysis contributes to fetal hepatic lipid accumulation and possibly to fetal overgrowth, at least in mice.
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Diabetes Gestacional , Humanos , Embarazo , Femenino , Ratones , Animales , Placenta , Esterol Esterasa , Hidrólisis , Ésteres del Colesterol , Glicerol , Macrosomía Fetal , Obesidad/complicaciones , Ácidos Grasos , Triglicéridos , LipasaRESUMEN
Maternal obesity causes metabolic dysfunction in the offspring, including dysbiosis, overeating, obesity, and type 2 diabetes. Early-life phases are fundamental for developing subcutaneous (SAT) and brown adipose tissues (BAT), handling energy excesses. Imaging of 18F-fluorodeoxyglucose by positron emission tomography (PET) and radiodensity by computerized tomography (CT) allows assessing adipose tissue (AT) whitening and browning in vivo and the underlying metabolic efficiency. Our aim was to examine these in vivo traits in SAT and BAT concerning gut microbiota composition in 1- and 6-month-old mice born to normal (NDoff) and high-fat diet-fed dams (HFDoff), accounting for body weight responses. We found low radiodensity (high lipids) in HFDoff SAT at 1 month, relating to an increased abundance of Dorea genus in the caecum and activation of the fatty acid biosynthetic pathway. Instead, low BAT radiodensity and glucose uptake were seen in adult HFDoff. Glucose was shifted in favor of BAT at 1 month and SAT at 6 months. In adults, unclassified Enterococcaceae and Rikenellaceae, and Bacillus genera were negatively related to BAT, whereas unclassified Clostridiales genera were related to SAT metabolism. Stratification of HFDoff based on weight-response, namely maternal induced obesity (MIO-HFDoff) or obesity-resistant (MIOR-HFDoff), showed sex dimorphism. Both subgroups were hyperphagic, but only obese mice had hyper-leptinemia and hyper-resistinemia, together with BAT dysfunction, whereas non-obese HFDoff had hyperglycemia and SAT hypermetabolism. In the caecum, unclassified Rikenellaceae (10-fold enrichment in MIO-HFDoff) and Clostridiales genera (4-fold deficiency in MIOR-HFDoff) were important discriminators of these two phenotypes. In conclusion, SAT whitening is an early abnormality in the offspring of HFD dams. In adult life, maternal HFD and the induced excessive food intake translates into a dimorphic phenotype involving SAT, BAT, and microbiota distinctively, reflecting maternal diet*sex interaction. This helps explain inter-individual variability in fetal programming and the higher rates of type 2 diabetes observed in adult women born to obese mothers, supporting personalized risk assessment, prevention, and treatment.
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Pre-pregnancy obesity and high-fat diet (HFD) during pregnancy and lactation are associated with neurodevelopmental delay in offspring. This study aimed to investigate whether milk fat globule membrane (MFGM) supplementation in obese dams could promote neurodevelopment in offspring. Obese female rats induced by HFD were supplemented with MFGM during pregnancy and lactation. Maternal HFD exposure significantly delayed the maturation of neurological reflexes and inhibited neurogenesis in offspring, which were significantly recovered by maternal MFGM supplementation. Gut microbiota analysis revealed that MFGM supplementation modulated the diversity and composition of gut microbiota in offspring. The abundance of pro-inflammatory bacteria such as Escherichia shigella and Enterococcus were down-regulated, and the abundance of bacteria with anti-inflammatory and anti-obesity functions, such as Akkermansia and Lactobacillus were up-regulated. Furthermore, MFGM alleviated neuroinflammation by decreasing the levels of lipopolysaccharides (LPS) and pro-inflammatory cytokines in the circulation and brain, as well as inhibiting the activation of microglia. Spearman's correlation analysis suggested that there existed a correlation between gut microbiota and inflammation-related indexes. In conclusion, maternal MFGM supplementation promotes neurodevelopment partly via modulating gut microbiota in offspring.
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The gut microbiota plays a critical role in energy homeostasis and its dysbiosis is associated with obesity. Maternal high-fat diet (HFD) and ß-adrenergic stimuli alter the gut microbiota independently; however, their collective regulation is not clear. To investigate the combined effect of these factors on offspring microbiota, 20-week-old offspring from control diet (17% fat)- or HFD (45% fat)-fed dams received an injection of either vehicle or ß3-adrenergic agonist CL316,243 (CL) for 7 days and then cecal contents were collected for bacterial community profiling. In a follow-up study, a separate group of mice were exposed to either 8 °C or 30 °C temperature for 7 days and blood serum and cecal contents were used for metabolome profiling. Both maternal diet and CL modulated the gut bacterial community structure and predicted functional profiles. Particularly, maternal HFD and CL increased the Firmicutes/Bacteroidetes ratio. In mice exposed to different temperatures, the metabolome profiles clustered by treatment in both the cecum and serum. Identified metabolites were enriched in sphingolipid and amino acid metabolism in the cecum and in lipid and energy metabolism in the serum. In summary, maternal HFD altered offspring's response to CL and altered microbial composition and function. An independent experiment supported the effect of thermogenic challenge on the bacterial function through metabolome change.
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Dieta Alta en Grasa , Microbioma Gastrointestinal , Animales , Dieta Alta en Grasa/efectos adversos , Estudios de Seguimiento , Metaboloma , Ratones , Ratones Endogámicos C57BLRESUMEN
Aim: Maternal high-fat diet (HFD) is associated with the development of cardiovascular disease (CVD) in adult offspring. Atherosclerotic vascular calcification is well documented in patients with CVD. We examined the effect of maternal HFD on calcified plaque formation. Methods and results: Seven-week-old female apo-E-/- mice (C57BL6/J) were nourished either an HFD or a normal diet (ND) a week before mating, and during gestation and lactation. Offspring of both the groups were fed a high-cholesterol diet (HCD) from 8 weeks of age. Osteogenic activity of the thoracic aorta, assessed using an ex vivo imaging system, was significantly increased after 3 months of HCD in male offspring of HFD-fed dams (O-HFD) as compared with those of ND-fed dams (O-ND). Alizarin-red-positive area in the aortic root was significantly increased after 6 months of HCD in male O-HFD as compared to that of O-ND. Plaque size and Oil Red O-positive staining were comparable between the two groups. Primary cultured vascular smooth muscle cells (VSMCs) of the thoracic aorta were treated with phosphate and interleukinL-1ß (IL-1ß) to transform them into an osteochondrocytic-like phenotype. Intracellular calcium content and alkaline phosphatase activity were markedly higher in the VSMCs of O-HFD than in O-ND. IL-1ß concentration in the supernatant of bone marrow-derived macrophages was markedly higher in O-HFD than in O-ND. Conclusion: Our findings indicate that maternal HFD accelerates the expansion of atherogenic calcification independent of plaque progression. In vitro phosphate- and IL-1ß-induced osteochondrocytic transformation of VSMCs was augmented in O-HFD. Inhibition of VSMCs, skewing toward osteochondrocytic-like cells, might be a potential therapeutic strategy for preventing maternal HFD-associated CVD development.
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A maternal high-fat diet affects offspring neurodevelopment with long-term consequences on their brain health and behavior. During the past three decades, obesity has rapidly increased in the whole human population worldwide, including women of reproductive age. It is known that maternal obesity caused by a high-fat diet may lead to neurodevelopmental disorders in their offspring, such as autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, depression, and schizophrenia. A maternal high-fat diet can affect offspring neurodevelopment due to inflammatory activation of the maternal gut, adipose tissue, and placenta, mirrored by increased levels of pro-inflammatory cytokines in both maternal and fetal circulation. Furthermore, a maternal high fat diet causes gut microbial dysbiosis further contributing to increased inflammatory milieu during pregnancy and lactation, thus disturbing both prenatal and postnatal neurodevelopment of the offspring. In addition, global molecular and cellular changes in the offspring's brain may occur due to epigenetic modifications including the downregulation of brain-derived neurotrophic factor (BDNF) expression and the activation of the endocannabinoid system. These neurodevelopmental aberrations are reflected in behavioral deficits observed in animals, corresponding to behavioral phenotypes of certain neurodevelopmental disorders in humans. Here we reviewed recent findings from rodent models and from human studies to reveal potential mechanisms by which a maternal high-fat diet interferes with the neurodevelopment of the offspring.
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Dysbiosis of gut microbiota can contribute to the progression of diabetes and obesity. Previous studies have shown that maternal high-fat (HF) diet during the perinatal period can alter the microbiota and induce metabolic disorders at weaning. However, whether dysbiosis of gut microbiota and metabolism could be recovered by a normal diet after weaning and the dynamic changes of gut microbiota have not been fully studied. In this study, C57BL/6J female mice were fed with a normal chow (NC) or HF diet for 4 weeks preconception, during gestation, and until pup weaning. After weaning, male offspring were fed with an NC diet until 9 weeks of age. The microbiota of offspring at weaning and 9 weeks of age was collected for 16S rRNA gene amplicon sequencing. We found that dams fed with an HF diet showed glucose intolerance after lactation. Compared with the offspring from NC dams, the offspring from HF dams exhibited a higher body weight, hyperglycemia, glucose intolerance, hyperinsulinemia, hypercholesterolemia, and leptin resistance and lower adiponectin at weaning. Fecal analysis indicated altered microbiota composition between the offspring of the two groups. The decrease in favorable bacteria (such as norank f Bacteroidales S24-7 group) and increase in unfavorable bacteria (such as Lachnoclostridium and Desulfovibrio) were strongly associated with a disturbance of glucose and lipid metabolism. After 6 weeks of normal diet, no difference in body weight, glucose, and lipid profiles was observed between the offspring of the two groups. However, the microbiota composition of offspring in the HF group was still different from that in the NC group, and microbiota diversity was lower in offspring of the HF group. The abundance of Lactobacillus was lower in the offspring of the HF group. In conclusion, a maternal HF diet can induce metabolic homeostasis and gut microbiota disturbance in offspring at weaning. Gut microbiota dysbiosis can persist into adulthood in the offspring, which might have a role in the promotion of susceptibility to obesity and diabetes in the later life of the offspring.