Background: The causes of the current obesity pandemic have not been fully elucidated. Implication of environmental endocrine disruptors such as bisphenol A (BPA) on adipose tissue development has ...been poorly investigated. Objectives: The aim of the present study was to evaluate the effects of perinatal exposure to BPA on early adipose storage at weaning. Methods: Pregnant Sprague-Dawley rats had access to drinking water containing 1mg/LBPA from day 6 of gestation through the end of lactation. Pups were weaned on postnatal day (PND) 21. At that time, we investigated perigonadal adipose tissue of pups (weight, histology, gene expression). For the remaining animals, we recorded body weight and food intake for animals on either standard chow or a high-fat diet. Results: Gestational exposure to BPA did not alter the sex ratio or litter size at birth. On PND1, the weight of male and female BPA-exposed pups was increased. On PND21, body weight was increased only in females, in which parametrial white adipose tissue (pWAT) weight was increased about 3-fold. This excess of pWAT was associated with adipocyte hypertrophy and overexpression of lipogenic genes such as C/EBP-α (CAAT enhancer binding protein alpha), PPAR-y (peroxisome proliferator-activated receptor gamma), SREBP-1C (sterol regulatory element binding protein-1C), LPL (lipoprotein lipase), FAS (fatty acid synthase), and SCD-1 (stearoyl-CoA desaturase 1). In addition, gene expression of SREBP-1C, FAS, and ACC (acetyl-CoA carboxylase) was also increased in liver from BPA-exposed females at PND21, without a change in circulating lipids and glucose. After weaning, perinatal BPA exposure predisposed to overweight in a sex-and diet-dependent manner. We observed no change in food intake due to perinatal BPA exposure in rats on either standard chow or a high-fat diet. Conclusions: Perinatal exposure to a low dose of BPA increased adipogenesis in females at weaning. Adult body weight may be programmed during early life, leading to changes dependent on the sex and the nutritional status. Although further studies are required to understand the mechanisms of BPA action in early life, these results are particularly important with regard to the increasing prevalence of childhood obesity and the context-dependent action of endocrine disruptors.
Injuries to the developing brain due to hypoxia–ischemia (HI) are common causes of neurological disabilities in preterm babies. HI, with oxygen deprivation to the brain or reduced cerebral blood ...perfusion due to birth asphyxia, often leads to severe brain damage and sequelae. Injury mechanisms include glutamate excitotoxicity, oxidative stress, blood–brain barrier dysfunction, and exacerbated inflammation. Nutritional intervention is emerging as a therapeutic alternative to prevent and rescue brain from HI injury. Lactoferrin (Lf) is an iron-binding protein present in saliva, tears, and breast milk, which has been shown to have antioxidant, anti-inflammatory and anti-apoptotic properties when administered to mothers as a dietary supplement during pregnancy and/or lactation in preclinical studies of developmental brain injuries. However, despite Lf’s promising neuroprotective effects, there is no established dose. Here, we tested three different doses of dietary maternal Lf supplementation using the postnatal day 3 HI model and evaluated the acute neurochemical damage profile using 1H Magnetic Resonance Spectroscopy (MRS) and long-term microstructure alterations using advanced diffusion imaging (DTI/NODDI) allied to protein expression and histological analysis. Pregnant Wistar rats were fed either control diet or bovine Lf supplemented chow at 0.1, 1, or 10 g/kg/body weight concentration from the last day of pregnancy (embryonic day 21–E21) to weaning. At postnatal day 3 (P3), pups from both sexes had their right common carotid artery permanently occluded and were exposed to 6% oxygen for 30 min. Sham rats had the incision but neither surgery nor hypoxia episode. At P4, MRS was performed on a 9.4 T scanner to obtain the neurochemical profile in the cortex. At P4 and P25, histological analysis and protein expression were assessed in the cortex and hippocampus. Brain volumes and ex vivo microstructural analysis using DTI/NODDI parameters were performed at P25. Acute metabolic disturbance induced in cortical tissue by HIP3 was reversed with all three doses of Lf. However, data obtained from MRS show that Lf neuroprotective effects were modulated by the dose. Through western blotting analysis, we observed that HI pups supplemented with Lf at 0.1 and 1 g/kg were able to counteract glutamatergic excitotoxicity and prevent metabolic failure. When 10 g/kg was administered, we observed reduced brain volumes, increased astrogliosis, and hypomyelination, pointing to detrimental effects of high Lf dose. In conclusion, Lf supplementation attenuates, in a dose-dependent manner, the acute and long-term cerebral injury caused by HI. Lf reached its optimal effects at a dose of 1 g/kg, which pinpoints the need to better understand effects of Lf, the pathways involved and possible harmful effects. These new data reinforce our knowledge regarding neuroprotection in developmental brain injury using Lf through lactation and provide new insights into lactoferrin’s neuroprotection capacities and limitation for immature brains.
Systemic hypoxia-ischemia (HI) often occurs during preterm birth in human. HI induces injuries to hinder brain cells mainly in the ipsilateral forebrain structures. Such HI injuries may cause ...lifelong disturbances in the distant regions, such as the contralateral side of the cerebellum. We aimed to evaluate behavior associated with the cerebellum, to acquire cerebellar abundant metabolic alterations using
H magnetic resonance spectroscopy (
H MRS), and to determine GFAP, NeuN, and MBP protein expression in the left cerebellum, in adult rats after mild early postnatal HI on the right forebrain at day 3 (PND3). From PND45, HI animals exhibited increased locomotion in the open field while there is neither asymmetrical forelimb use nor coordination deficits in the motor tasks. Despite the fact that metabolic differences between two cerebellar hemispheres were noticeable, a global increase in glutamine of HI rats was observed and became significant in the left cerebellum compared to the sham-operated group. Furthermore, increases in glutamate, glycine, the sum of glutamate and glutamine and total choline, only occurred in the left cerebellum of HI rats. Remarkably, there were decreased expression of MBP and NeuN but no detectable reactive astrogliosis in the contralateral side of the cerebellum of HI rats. Taken together, the detected alterations observed in the left cerebellum of HI rats may reflect disequilibrium in the glutamate-glutamine cycle and a delay in the return of glutamine from astrocytes to neurons from hypoxic-ischemic origin. Our data provides
evidence of long-term changes in the corresponding cerebellum following mild neonatal HI in very immature rats, supporting the notion that systemic HI could cause cell death in the cerebellum, a distant region from the expected injury site.
-Neonatal hypoxia-ischemia (HI) in very immature rats induces hyperactivity toward adulthood.-
H magnetic resonance spectroscopy detects long-term cerebellar metabolic changes in adult rats after neonatal HI at postnatal day 3.-Substantial decreases of expression of neuronal and myelin markers in adult rats cerebellum after neonatal cortical mild HI.
Type 1 diabetes (T1DM) results from destruction of most insulin-secreting pancreatic β-cells. The persistence of β-cells decades after the onset of the disease indicates that the resistance of ...individual cells to the autoimmune insult is heterogeneous and might depend on the metabolic status of a cell at a given moment. The aim of this study is to investigate whether activation of nicotinic acetylcholine receptors (nACh-Rs) could increase β-cell resistance against the adverse environment prevailing at the onset of T1DM. Here, we show that nACh-R activation by nicotine and choline, 2 agonists of the receptor, decreases murine and human β-cell apoptosis induced by proinflammatory cytokines known to be present in the islet environment at the onset of T1DM. The protective mechanism activated by nicotine and choline involves attenuation of mitochondrial outer membrane permeabilization via modulation of endoplasmic reticulum stress, of the activity of B-cell lymphoma 2 family proteins and cytoplasmic calcium levels. Local inflammation and endoplasmic reticulum stress being key determinants of β-cell death in T1DM, we conclude that pharmacological activation of nACh-R could represent a valuable therapeutic option in the modulation of β-cell death in T1DM.
Intrauterine Growth Restriction (IUGR) refers to an impaired development of the fetus and hence results in adverse neurodevelopmental and psychiatric consequences later in life. Lactoferrin (Lf) is a ...glycoprotein present in milk that has already shown neuroprotective effects through its anti-inflammatory and antioxidant properties on impaired developing brains. The aim of this study was to characterize a rat model of IUGR and assess the neuroprotective effect of a nutritional supplementation with bovine Lf during pregnancy and lactation on this model.
A model of 50% gestational caloric restriction (CR) was used. Three groups were designed, and pregnant rats had either
access to food (control group, CTL) or 50% of the controls' intake (restricted group, IUGR). The diet was isocaloric and supplemented with bovine Lf for the caloric restricted dams (restricted-Lf, IUGR_Lf). At postnatal day 7 and 21, advanced
diffusion MRI techniques at 9.4T were used to investigate brain cortical and white matter microstructure. Further, genes and proteins involved in structure (synaptophysin, MBP), microglia (Iba-1), metabolism (MCT2, βCaMKII) and apoptosis (Bcl-2) were analyzed in the cortex and striatum. In the cortex, the number of parvalbumin immunoreactive interneurons and their perineuronal nets were quantified. Behavioral tests were performed at P31.
Effects of the CR were significant in the cortex and striatum with reduction of synaptophysin (marker of synaptogenesis) at P7 and MBP (marker of myelin) at P21 in the cortex. Indeed, MCT2 (energy metabolism), Bcl-2 (anti-apoptotic protein) and βCaMKII (synapse activity) expressions were reduced in IUGR groups at P7. In the striatum NG2 (marker of oligodendrocyte precursor cells) and Bcl-2 at P7 as well as βCaMKII at P21 were decreased following IUGR and restored by Lf. Cortical microstructure was impaired following CR with partial effect of Lf. Lf prevented oxidative stress induced parvalbumin interneurons impairments whereas striatum and external capsule showed alterations in microstructure depicted by diffusion MRI, which were also partially reversed by Lf.
The model of 50% caloric restriction induced mild impairment partially reversed by nutritional intervention using Lf during pregnancy and lactation.
Poor fetal growth, also known as intrauterine growth restriction (IUGR), is a worldwide health concern. IUGR is commonly associated with both an increased risk in perinatal mortality and a higher ...prevalence of developing chronic metabolic diseases later in life. Obesity, type 2 diabetes or metabolic syndrome could result from noxious "metabolic programming." In order to better understand early alterations involved in metabolic programming, we modeled IUGR rat pups through either prenatal exposure to synthetic glucocorticoid (dams infused with dexamethasone 100 µg/kg/day, DEX) or prenatal undernutrition (dams feeding restricted to 30% of ad libitum intake, UN). Physiological (glucose and insulin tolerance), morphometric (automated tissue image analysis) and transcriptomic (quantitative PCR) approaches were combined during early life of these IUGR pups with a special focus on their endocrine pancreas and adipose tissue development. In the absence of catch-up growth before weaning, DEX and UN IUGR pups both presented basal hyperglycaemia, decreased glucose tolerance, and pancreatic islet atrophy. Other early metabolic defects were model-specific: DEX pups presented decreased insulin sensitivity whereas UN pups exhibited lowered glucose-induced insulin secretion and more marked alterations in gene expression of pancreatic islet and adipose tissue development regulators. In conclusion, these results show that before any catch-up growth, IUGR rats present early physiologic, morphologic and transcriptomic defects, which can be considered as initial mechanistic basis of metabolic programming.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels well characterized in neuronal signal transmission. Moreover, recent studies have revealed nAChR expression in ...nonneuronal cell types throughout the body, including tissues involved in metabolism. In the present study, we screen gene expression of nAChR subunits in pancreatic islets and adipose tissues. Mice pancreatic islets present predominant expression of α7 and β2 nAChR subunits but at a lower level than in central structures. Characterization of glucose and energy homeostasis in α7β2nAChR−/− mice revealed no major defect in insulin secretion and sensitivity but decreased glycemia apparently unrelated to gluconeogenesis or glycogenolysis. α7β2nAChR−/− mice presented an increase in lean and bone body mass and a decrease in fat storage with normal body weight. These observations were associated with elevated spontaneous physical activity in α7β2nAChR−/− mice, mainly due to elevation in fine vertical (rearing) activity while their horizontal (ambulatory) activity remained unchanged. In contrast to α7nAChR−/− mice presenting glucose intolerance and insulin resistance associated to excessive inflammation of adipose tissue, the present metabolic phenotyping of α7β2nAChR−/− mice revealed a metabolic improvement possibly linked to the increase in spontaneous physical activity related to central β2nAChR deficiency.
•α7 and β2 were the nAChR subunits most predominantly expressed in mice pancreatic islets but at a lower level than in central structures.•α7β2nAChR−/− mice present dampened basal glycemia but no change in insulin secretion and insulin sensitivity.•α7β2nAChR−/− mice present normal body weight, slight hyperphagia and decreased fat pad weight.•This lean phenotype can be explained by an increase in spontaneous physical activity observed in α7β2nAChR−/− mice possibly due to nAChR deficiency in central structures.
Prematurity, through brain injury and altered development is a major cause of neurological impairments and can result in motor, cognitive and behavioral deficits later in life. Presently, there are ...no well-established effective therapies for preterm brain injury and the search for new strategies is needed. Intra-uterine environment plays a decisive role in brain maturation and interventions using the gestational window have been shown to influence long-term health in the offspring. In this study, we investigated whether pregnancy swimming can prevent the neurochemical metabolic alterations and damage that result from postnatal hypoxic-ischemic brain injury (HI) in very immature rats.
Female pregnant Wistar rats were divided into swimming (SW) or sedentary (SE) groups. Following a period of adaptation before mating, swimming was performed during the entire gestation. At postnatal day (PND3), rat pups from SW and SE dams had right common carotid artery occluded, followed by systemic hypoxia. At PND4 (24 h after HI), the early neurochemical profile was measured by
H-magnetic resonance spectroscopy. Astrogliosis, apoptosis and neurotrophins protein expression were assessed in the cortex and hippocampus. From PND45, behavioral testing was performed. Diffusion tensor imaging and neurite orientation dispersion and density imaging were used to evaluate brain microstructure and the levels of proteins were quantified.
Pregnancy swimming was able to prevent early metabolic changes induced by HI preserving the energetic balance, decreasing apoptotic cell death and astrogliosis as well as maintaining the levels of neurotrophins. At adult age, swimming preserved brain microstructure and improved the performance in the behavioral tests.
Our study points out that swimming during gestation in rats could prevent prematurity related brain damage in progeny with high translational potential and possibly interesting cost-benefits.
- Prematurity is a major cause of neurodevelopmental impairments;- Swimming during pregnancy reduces brain damage after HI injury;- Pregnancy is an important but underestimated preventive window.
•Maternal immune challenge associated to perinatal anoxia and hindlimbs sensorimotor restriction in rats leads to musculoskeletal and brain damage observed in spastic Cerebral Palsy.•We show that one ...week exposure to environmental enrichment combined to 15 min daily treadmill training (EETT) from P21 to P28 improved gross locomotion with minor effects on gait parameters.•EETT decreased brain inflammation and astrogliosis, preserved myelination, without major effects on brain microstructure.•EETT upregulated BDNF signaling and modulated the expression of proteins involved in excitatory synaptic function in brain and spinal cord.
Cerebral Palsy (CP) is a major cause of motor and cognitive disability in children due to injury to the developing brain. Early intensive sensorimotor rehabilitation has been shown to change brain structure and reduce CP symptoms severity. We combined environmental enrichment (EE) and treadmill training (TT) to observe the effects of a one-week program of sensorimotor stimulation (EETT) in animals exposed to a CP model and explored possible mechanisms involved in the functional recovery.
Pregnant Wistar rats were injected with Lipopolysaccharide (LPS − 200 µg/kg) intraperitoneally at embryonic days 18 and 19. At P0, pups of both sexes were exposed to 20′ anoxia at 37 °C. From P2 to P21, hindlimbs were restricted for 16 h/day during the dark cycle. EETT lasted from P21 to P27. TT − 15 min/day at 7 cm/s. EE − 7 days in enriched cages with sensorimotor stimulus. Functional 3D kinematic gait analysis and locomotion were analyzed. At P28, brains were collected for ex-vivo MRI and histological assessment. Neurotrophins and key proteins involved in CNS function were assessed by western blotting.
CP model caused gross and skilled locomotor disruption and altered CNS neurochemistry. EETT reversed locomotor dysfunction with minor effects over gait kinematics. EETT also decreased brain inflammation and glial activation, preserved myelination, upregulated BDNF signaling and modulated the expression of proteins involved in excitatory synaptic function in the brain and spinal cord.
Using this translational approach based on intensive sensorimotor rehabilitation, we highlight pathways engaged in the early developmental processes improving neurological recovery observed in CP.
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