RESUMEN
Maternal nutrient intake influences the health of the offspring via microenvironmental systems in digestion and absorption. Maternal high fructose diet (HFD) impairs hippocampus-dependent memory in adult female rat offspring. However, the underlying mechanisms remain largely unclear. Maternal HFD causes microbiota dysbiosis. In this study, we find that the plasma level of butyrate, a major metabolite of microbiota, is significantly decreased in the adult female maternal HFD offspring. In these rats, GPR43, a butyrate receptor was downregulated in the hippocampus. Moreover, the expressions of mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) were downregulated in the hippocampus. The decreases of these functional proteins were reversed by fructooligosaccharides (FOS, a probiotic) treatment in adulthood. Astrocytes are critical for energy metabolism in the brain. Primary astrocyte culture from female maternal HFD offspring indicated that GPR43 and the mitochondrial biogenesis were significantly suppressed, which was reversed by supplemental butyrate incubation. The oxygen consumption rate (OCR) was reduced in the HFD group and rescued by butyrate. Intriguingly, the nuclear histone deacetylase 4 (HDAC4) was enhanced in the HFD group, suggesting an inhibitory role of butyrate on histone deacetylase activity. Inhibition of HDAC4 effectively restored the OCR, bioenergetics, and biogenesis of mitochondria. Together, these results suggested that the impaired butyrate signaling by maternal HFD could underlie the reduced mitochondrial functions in the hippocampus via HDAC4-mediated epigenetic changes.
Asunto(s)
Astrocitos , Butiratos , Femenino , Animales , Ratas , Butiratos/farmacología , Metabolismo Energético , Consumo de Oxígeno , Histona Desacetilasas , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Dieta Alta en GrasaRESUMEN
The role of short-chain fatty acids (SCFAs) in the brain on the developmental programming of hypertension is poorly understood. The present study explored dysregulated tissue levels of SCFAs and expression of SCFA-sensing receptors in the hypothalamic paraventricular nucleus (PVN), a key forebrain region engaged in neural regulation of blood pressure of offspring to maternal high fructose diet (HFD) exposure. We further investigated the engagement of SCFA-sensing receptors in PVN in the beneficial effects of -biotics (prebiotic, probiotic, synbiotic, and postbiotic) on programmed hypertension. Maternal HFD during gestation and lactation significantly reduced circulating butyrate, along with decreased tissue level of butyrate and increased expression of SCFA-sensing receptors, GPR41 and olfr78, and tissue oxidative stress and neuroinflammation in PVN of HFD offspring that were rectified by oral supplement with -biotics. Gene silencing of GPR41 or olfr78 mRNA in PVN also protected adult HFD offspring from programmed hypertension and alleviated the induced oxidative stress and inflammation in PVN. In addition, oral supplement with postbiotic butyrate restored tissue butyrate levels, rectified expressions of GPR41 and olfr78 in PVN, and protected against programmed hypertension in adult HFD offspring. These data suggest that alterations in tissue butyrate level, expression of GPR41 and olfr78, and activation of SCFA-sensing receptor-dependent tissue oxidative stress and neuroinflammation in PVN could be novel mechanisms that underlie hypertension programmed by maternal HFD exposure in adult offspring. Furthermore, oral -biotics supplementation may exert beneficial effects on hypertension of developmental origin by targeting dysfunctional SCFA-sensing receptors in PVN to exert antioxidant and anti-inflammatory actions in the brain.
Asunto(s)
Hipertensión , Núcleo Hipotalámico Paraventricular , Animales , Ratas , Femenino , Humanos , Núcleo Hipotalámico Paraventricular/metabolismo , Fructosa/efectos adversos , Fructosa/metabolismo , Antioxidantes/metabolismo , Ratas Sprague-Dawley , Hipertensión/prevención & control , Hipertensión/genética , Ácidos Grasos Volátiles/metabolismo , Dieta , Antiinflamatorios/metabolismo , ARN Mensajero/metabolismo , Butiratos/metabolismoRESUMEN
Retinopathy is a leading cause of blindness, and there is currently no cure. Earlier identification of the progression of retinopathy could provide a better chance for intervention. Diet has profound effects on retinal function. A maternal high-fructose diet (HFD) triggers diseases in multiple organs. However, whether maternal HFD impairs retinal function in adult offspring is currently unknown. By using the rodent model of maternal HFD during pregnancy and lactation, our data indicated a reduced b-wave of electroretinography (ERG) in HFD female offspring at 3 mo of age compared with age-matched offspring of dams fed regular chow (ND). Immunofluorescence and Western blot analyses indicated that the distributions and expressions of synaptophysin, postsynaptic density protein 95 (PSD95), and phospho(p)-Ca2+/calmodulin-stimulated protein kinase IIα (CaMKIIα) were significantly suppressed in the HFD group. Furthermore, the ATP content and the mitochondrial respiratory protein, Mt CPX 4-2, were decreased. Moreover, the expressions of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the retina of the HFD group were downregulated. Treatment with coenzyme Q10 (Q10), a key mediator of the electron transport chain, effectively reversed these abovementioned dysfunctions. Together, these results suggested that maternal HFD impaired retinal function in adult female offspring. The mechanism underlying early-onset retinopathy may involve the reduction in the capacity of mitochondrial energy production and the suppression of synaptic plasticity. Most importantly, mitochondria could be a feasible target to reprogram maternal HFD-damaged retinal function.NEW & NOTEWORTHY In this study, we provide novel evidence that maternal high-fructose diet during gestation and lactation could induce early-onset retinopathy in adult female offspring. Of note, the insufficient energy content, downregulated mitochondrial respiratory complex 4-2, and impaired mitochondrial biogenesis might contribute to the decrease of synaptic plasticity resulting in retinal function suppression. Oral application with coenzyme Q10 for 4 wk could at least partially reverse the aforementioned molecular events and retinal function.
Asunto(s)
Fructosa/efectos adversos , Mitocondrias/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Enfermedades de la Retina/inducido químicamente , Factores de Edad , Animales , Dieta Alta en Grasa/efectos adversos , Carbohidratos de la Dieta/efectos adversos , Carbohidratos de la Dieta/farmacología , Regulación hacia Abajo/efectos de los fármacos , Femenino , Fructosa/farmacología , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Mitocondrias/fisiología , Biogénesis de Organelos , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Ratas Sprague-Dawley , Enfermedades de la Retina/fisiopatologíaRESUMEN
Maternal high-fructose diets (HFD) impair the learning and memory capacity of adult female offspring via histone deacetylase 4 (HDAC4). Hippocampal adult neurogenesis is important for supporting the function of existing neural circuits. In this study, we investigated the effects of maternal HFD on hippocampal neural stem cell (NSC) proliferation and neuronal differentiation in adult offspring. Increased nuclear HDAC4 enzyme activity was detected in the hippocampus of HFD female offspring. The Western blot analyses indicated that the expressions of sex-determining region Y box2 (SOX2) and the transcription factor Paired Box 6 (PAX6), which are critical for the progression of NSC proliferation and differentiation, were downregulated. Concurrently, the expression of Ki67 (a cellular marker for proliferation) and doublecortin (DCX), which are related to NSC division and neuronal differentiation, was suppressed. Intracerebroventricular infusion with class II HDAC inhibitor (Mc1568, 4 weeks) led to the upregulation of these proteins. Environmental stimulation reversed the expression of Ki67 and DCX and the counts of Ki67- and DCX-positive cells in the hippocampi of HFD offspring as a result of providing the enriched housing for 4 weeks. Together, these results demonstrate that the suppressive effects of maternal HFD on hippocampal NSC proliferation and neuronal differentiation are reversibly mediated through HDAC4 and can be effectively reversed by environmental stimulation. The advantageous effects of environmental enrichment were possibly mediated by HDAC4 suppression.
Asunto(s)
Giro Dentado , Dieta , Fructosa , Histona Desacetilasas , Adulto , Diferenciación Celular , Proliferación Celular , Femenino , Hipocampo , Humanos , NeurogénesisRESUMEN
The mechanisms beneath the initiation of neuroinflammation are still inconclusive. Growing evidence proposes the maternal effect on the development of neuroinflammation. In this study, we evaluated the upstream regulators and the indices of neuroinflammation in the hippocampi of female offspring at 3 months old. The accumulation of nuclear factor-κB (NF-κB, 65 kDa), a cytokine-encoding transcription factor, was increased in microglia. The enhanced microglial activation was detected in CA1, CA3 and dentate gyrus (DG) HFD group with upregulation of CD11b and ionized calcium binding adaptor molecule 1 (Iba-1). Moreover, proinflammatory cytokines (including TNFα, IL-1ß and IL-6) were significantly increased in HFD group. Peroxisome proliferator-activated receptors γ (PPARγ) is a transcription factor involved in the suppression of NF-κB expression and in encoding endogenous antioxidants (such as catalase and glutathione peroxidases). On the contrary, the expression of nuclear PPARγ was suppressed in hippocampal neurons of the HFD group. In addition, the expressions of glutathione peroxidase 1 (GPx1) was suppressed in HFD group. Oral application with pioglitazone, a PPARγ agonist, effectively ceased the neuroinflammation and reversed the expression of antioxidants in HFD group. Together, these results for the first time demonstrated that maternal HFD triggered the waxing and waning of NF-κB and PPARγ may initiate neuroinflammation in the hippocampus of adult female offspring. Our findings further suggest that PPARγ could be the feasible targets to reprogram the hippocampal impairment induced by maternal HFD.
Asunto(s)
Fructosa/farmacología , Hipocampo/metabolismo , Inflamación/metabolismo , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Animales , Citocinas/metabolismo , Dieta/métodos , Femenino , Fructosa/efectos adversos , Hipocampo/efectos de los fármacos , Inflamación/etiología , Mediadores de Inflamación/metabolismo , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Inflamación Neurogénica , Neuronas/metabolismo , Pioglitazona/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Excessive maternal high-fructose diet (HFD) during pregnancy and lactation has been reported to cause metabolic disorders in the offspring. Whether the infant's brain metabolism is disturbed by maternal HFD is largely unknown. Brain energy metabolism is elevated dramatically during fetal and postnatal development, whereby maternal nutrition is a key factor that determines cellular metabolism. Astrocytes, a nonneuronal cell type in the brain, are considered to support the high-energy demands of neurons by supplying lactate. In this study, the effects of maternal HFD on astrocytic glucose metabolism were investigated using hippocampal primary cultures of female infants. We found that glycolytic capacity and mitochondrial respiration and electron transport chain were suppressed by maternal HFD. Mitochondrial DNA copy number and mitochondrial transcription factor A expression were suppressed by maternal HFD. Western blots and immunofluorescent images further indicated that the glucose transporter 1 was downregulated whereas the insulin receptor-α, phospho-insulin receptor substrate-1 (Y612) and the p85 subunit of phosphatidylinositide 3-kinase were upregulated in the HFD group. Pioglitazone, which is known to increase astrocytic glucose metabolism, effectively reversed the suppressed glycolysis, and lactate release was restored. Moreover, pioglitazone also normalized oxidative phosphorylation with an increase of cytosolic ATP. Together, these results suggest that maternal HFD impairs astrocytic energy metabolic pathways that were reversed by pioglitazone.
Asunto(s)
Astrocitos/efectos de los fármacos , Azúcares de la Dieta/farmacología , Fructosa/farmacología , Glucólisis/efectos de los fármacos , Hipoglucemiantes/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Pioglitazona/farmacología , Animales , Astrocitos/metabolismo , ADN Mitocondrial/efectos de los fármacos , ADN Mitocondrial/metabolismo , Femenino , Desarrollo Fetal , Transportador de Glucosa de Tipo 1/efectos de los fármacos , Transportador de Glucosa de Tipo 1/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Cultivo Primario de Células , Ratas , Receptor de Insulina/efectos de los fármacos , Receptor de Insulina/metabolismo , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/metabolismoRESUMEN
Impairment of learning and memory has been documented in the later life of offspring to maternal consumption with high energy diet. Environmental stimulation enhances the ability of learning and memory. However, potential effects of environmental stimulation on the programming-associated deficit of learning and memory have not been addressed. Here, we examined the effects of enriched-housing on hippocampal learning and memory in adult female offspring rats from mother fed with 60% high fructose diet (HFD) during pregnancy and lactation. Impairment of spatial learning and memory performance in HFD group was observed in offspring at 3-month-old. Hippocampal brain-derived neurotrophic factor (BDNF) was decreased in the offspring. Moreover, the HFD group showed an up-regulation of histone deacetylase 4 (HDAC4) in the nuclear fractions of hippocampal neurons. Stimulation to the offspring for 4weeks after winning with an enriched-housing environment effectively rescued the decrease in cognitive function and hippocampal BDNF level; alongside a reversal of the increased distribution of nuclear HDAC4. Together these results suggest that later life environmental stimulation effectively rescues the impairment of hippocampal learning and memory in female offspring to maternal HFD intake through redistributing nuclear HDAC4 to increase BDNF expression.