Maternal One-Carbon Nutrient Intake and Risk of Being Overweight or Obese in Their Offspring-A Transgenerational Prospective Cohort Study.

We aimed to investigate the associations between maternal intake of folate, vitamin B12, B6, B2, methionine, choline, phosphatidylcholine and betaine during the period surrounding pregnancy and offspring weight outcomes from birth to early adulthood. These associations were examined among 2454 mother-child pairs from the Nurses' Health Study II and Growing Up Today Study. Maternal energy-adjusted nutrient intakes were derived from food frequency questionnaires. Birth weight, body size at age 5 and repeated BMI measurements were considered. Overweight/obesity was defined according to the International Obesity Task Force (<18 years) and World Health Organization guidelines (18+ years). Among other estimands, we report relative risks (RRs) for offspring ever being overweight with corresponding 95% confidence intervals across quintiles of dietary factors, with the lowest quintile as the reference. In multivariate-adjusted models, higher maternal intakes of phosphatidylcholine were associated with a higher risk of offspring ever being overweight (RRQ5vsQ1 = 1.16 [1.01-1.33] p-trend: 0.003). The association was stronger among offspring born to mothers with high red meat intake (high red meat RRQ5vsQ1 = 1.50 [1.14-1.98], p-trend: 0.001; low red meat RRQ5vsQ1 = 1.05 [0.87-1.27], p-trend: 0.46; p-interaction = 0.13). Future studies confirming the association between a higher maternal phosphatidylcholine intake during pregnancy and offspring risk of being overweight or obese are needed.

Effects of sociocultural stressors on maternal responsivity and the infant behavioral and neuroendocrine response to stress in families of Mexican descent.

Maternal stress is consistently linked to alterations in maternal behavior and infant neurodevelopmental outcomes. As the Latino population grows in the U.S., it is increasingly important to understand how culturally relevant factors affect this relationship. This study aimed to address the role of sociocultural stressors on maternal sensitivity and markers of infant emotional regulation and the neuroendocrine response to stress in mother/infant dyads of Mexican descent. Pregnant women of Mexican descent (n = 115) were recruited during early pregnancy and followed until their infants were 6 months old. Mothers completed measures of sociocultural stressors (acculturative stress and discrimination) at pre and postnatal time points. At 6 months, dyads underwent the Still Face procedure. Mothers were observed for behaviors exhibiting maternal responsivity, while negative vocalizations were observed in infants. Salivary cortisol was also collected from infants. Maternal responsivity was a salient risk factor for alterations in infant emotional regulation and cortisol activity. Postnatal experiences of discrimination were also negatively associated with infant negative affect. This work highlights maternal responsivity and points to a potential role for experiences of discrimination in the response to stress in the mother/child dyad that may have consequences for the development of emotional regulation in infants of Mexican descent.

Alterations of materno-placento-fetal glucose homeostasis after a single course of antenatal betamethasone.

INTRODUCTION: Intrauterine growth impairment is associated with long-term metabolic changes (perinatal programming). We recently demonstrated that antenatal betamethasone (BET) decreased head circumference in term born females. Since glucose is the main energy source for fetal growth, BET-induced changes in maternal glucose homeostasis, a reduced transplacental glucose transfer or an altered fetal glucose utilization may be linked with the observed growth impairment. METHODS: 86 pregnant women exposed to BET (single course, <34 + 0 weeks of gestation (wks)) were compared to 92 gestational-age/sex-matched controls. Glucose, insulin, leptin, insulin-like growth factors (IGF-1, IGF-2) and their binding proteins (IGFBP-1, IGFBP-3) were measured in maternal and umbilical cord blood samples. Homeostasis Model Assessment (HOMA-IR) was calculated. Placental glucose transporter 1 and 3 (GLUT1, GLUT3) protein levels were determined. Statistics were performed for overall and subgroup analysis (gestational age, sex). RESULTS: After BET maternal HOMA-IR was elevated, IGFBP-1 reduced. In female pregnancies, glucose levels ≥37 + 0 wks and IGF-1 levels <37 + 0 wks were tendentially increased. Placental GLUT1 and GLUT3 protein levels were not significantly altered. Fetal umbilical venous glucose levels ≥37 + 0 wks were increased. HOMA-IR tended to be elevated in females. DISCUSSION: Growth impairment after BET appears neither caused by maternal nor fetal hypoglycemia nor changes of GLUT1 and GLUT3 total protein levels. Nonetheless, glucose homeostasis of mothers and daughters was altered even beyond the BET time frame (hyperglycemia, enhanced insulin resistance). Despite glucose supply was sufficient, an anabolic effect was apparently absent. Overall, our results highlight the relevance of adequate glucose management after BET and peripartum.

Pathomechanisms of Prenatally Programmed Adult Diseases.

Based on epidemiological observations Barker et al. put forward the hypothesis/concept that an adverse intrauterine environment (involving an insufficient nutrient supply, chronic hypoxia, stress, and toxic substances) is an important risk factor for the development of chronic diseases later in life. The fetus responds to the unfavorable environment with adaptive reactions, which ensure survival in the short run, but at the expense of initiating pathological processes leading to adult diseases. In this review, the major mechanisms (including telomere dysfunction, epigenetic modifications, and cardiovascular-renal-endocrine-metabolic reactions) will be outlined, with a particular emphasis on the role of oxidative stress in the fetal origin of adult diseases.

Circadian glucocorticoids throughout development.

Glucocorticoids (GCs) are essential drivers of mammalian tissue growth and maturation during one of the most critical developmental windows, the perinatal period. The developing circadian clock is shaped by maternal GCs. GC deficits, excess, or exposure at the wrong time of day leads to persisting effects later in life. During adulthood, GCs are one of the main hormonal outputs of the circadian system, peaking at the beginning of the active phase (i.e., the morning in humans and the evening in nocturnal rodents) and contributing to the coordination of complex functions such as energy metabolism and behavior, across the day. Our article discusses the current knowledge on the development of the circadian system with a focus on the role of GC rhythm. We explore the bidirectional interaction between GCs and clocks at the molecular and systemic levels, discuss the evidence of GC influence on the master clock in the suprachiasmatic nuclei (SCN) of the hypothalamus during development and in the adult system.

Maternal overnutrition is associated with altered synaptic input to lateral hypothalamic area.

OBJECTIVE: Maternal overnutrition is associated with adverse outcomes in offspring, including increased risk for obesity and diabetes. Here, we aim to test the effects of maternal obesity on lateral hypothalamic feeding circuit function and determine the relationship with body weight regulation. METHODS: Using a mouse model of maternal obesity, we assessed how perinatal overnutrition affected food intake and body weight regulation in adult offspring. We then used channelrhodopsin-assisted circuit mapping and electrophysiological recordings to assess the synaptic connectivity within an extended amygdala-lateral hypothalamic pathway. RESULTS: We show that maternal overnutrition during gestation and throughout lactation produces offspring that are heavier than controls prior to weaning. When weaned onto chow, the body weights of over-nourished offspring normalize to control levels. However, when presented with highly palatable food as adults, both male and female maternally over-nourished offspring are highly susceptible to diet-induced obesity. This is associated with altered synaptic strength in an extended amygdala-lateral hypothalamic pathway, which is predicted by developmental growth rate. Additionally, lateral hypothalamic neurons receiving synaptic input from the bed nucleus of the stria terminalis have enhanced excitatory input following maternal overnutrition which is predicted by early life growth rate. CONCLUSIONS: Together, these results demonstrate one way in which maternal obesity rewires hypothalamic feeding circuits to predispose offspring to metabolic dysfunction.

Nutrition and adult neurogenesis in the hippocampus: Does what you eat help you remember?

Neurogenesis is a complex process by which neural progenitor cells (NPCs)/neural stem cells (NSCs) proliferate and differentiate into new neurons and other brain cells. In adulthood, the hippocampus is one of the areas with more neurogenesis activity, which is involved in the modulation of both emotional and cognitive hippocampal functions. This complex process is affected by many intrinsic and extrinsic factors, including nutrition. In this regard, preclinical studies performed in rats and mice demonstrate that high fats and/or sugars diets have a negative effect on adult hippocampal neurogenesis (AHN). In contrast, diets enriched with bioactive compounds, such as polyunsaturated fatty acids and polyphenols, as well as intermittent fasting or caloric restriction, can induce AHN. Interestingly, there is also growing evidence demonstrating that offspring AHN can be affected by maternal nutrition in the perinatal period. Therefore, nutritional interventions from early stages and throughout life are a promising perspective to alleviate neurodegenerative diseases by stimulating neurogenesis. The underlying mechanisms by which nutrients and dietary factors affect AHN are still being studied. Interestingly, recent evidence suggests that additional peripheral mediators may be involved. In this sense, the microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could act as a link between nutritional factors and AHN. The aim of this mini-review is to summarize, the most recent findings related to the influence of nutrition and diet in the modulation of AHN. The importance of maternal nutrition in the AHN of the offspring and the role of the microbiota-gut-brain axis in the nutrition-neurogenesis relationship have also been included.

Effects of Voluntary Sodium Consumption during the Perinatal Period on Renal Mechanisms, Blood Pressure, and Vasopressin Responses after an Osmotic Challenge in Rats.

Cardiovascular control is vulnerable to forced high sodium consumption during the per-inatal period, inducing programming effects, with anatomical and molecular changes at the kidney, brain, and vascular levels that increase basal and induce blood pressure. However, the program- ming effects of the natriophilia proper of the perinatal period on blood pressure control have not yet been elucidated. In order to evaluate this, we studied the effect of a sodium overload challenge (SO) on blood pressure response and kidney and brain gene expression in adult offspring exposed to voluntary hypertonic sodium consumption during the perinatal period (PM-NaCl group). Male PM-NaCl rats showed a more sustained increase in blood pressure after SO than controls (PM-Ctrol). They also presented a reduced number of glomeruli, decreased expression of TRPV1, and increased expression of At1a in the kidney cortex. The relative expression of heteronuclear vaso- pressin (AVP hnRNA) and AVP in the supraoptic nucleus was unchanged after SO in PM-NaCl in contrast to the increase observed in PM-Ctrol. The data indicate that the availability of a rich source of sodium during the perinatal period induces a long-term effect modifying renal, cardiovascular, and neuroendocrine responses implicated in the control of hydroelectrolyte homeostasis.

The Metabolically Obese, Normal-Weight Phenotype in Young Rats Is Associated with Cognitive Impairment and Partially Preventable with Leptin Intake during Lactation.

The intake of high-fat diets (HFDs) and obesity are linked to cognitive impairment. Here, we aimed to investigate whether an early metabolically obese, normal-weight (MONW) phenotype, induced with an HFD in young rats, also leads to cognitive dysfunction and to evaluate the potential cognitive benefits of neonatal intake of leptin. To achieve this, Wistar rats orally received physiological doses of leptin or its vehicle during lactation, followed by 11 weeks of pair-feeding with an HFD or control diet post-weaning. Working memory was assessed using a T-maze, and gene expression in the hippocampus and peripheral blood mononuclear cells (PBMCs) was assessed with real-time RT-qPCR to identify cognition biomarkers. Young MONW-like rats showed hippocampal gene expression changes and decreased working memory. Animals receiving leptin during lactation presented similar gene expression changes but preserved working memory despite HFD intake, partly due to improved insulin sensitivity. Notably, PBMC Syn1 expression appears as an accessible biomarker of cognitive health, reflecting both the detrimental effect of HFD intake at early ages despite the absence of obesity and the positive effects of neonatal leptin treatment on cognition. Thus, the MONW phenotype developed at a young age is linked to cognitive dysfunction, which is reflected at the transcriptomic level in PBMCs. Neonatal leptin intake can partly counteract this impaired cognition resulting from early HFD consumption.

Elevated n-3/n-6 PUFA ratio in early life diet reverses adverse intrauterine kidney programming in female rats.

Intrauterine growth restriction (IUGR) predisposes to chronic kidney disease via activation of proinflammatory pathways, and omega-3 PUFAs (n-3 PUFAs) have anti-inflammatory properties. In female rats, we investigated 1) how an elevated dietary n-3/n-6 PUFA ratio (1:1) during postnatal kidney development modifies kidney phospholipid (PL) and arachidonic acid (AA) metabolite content and 2) whether the diet counteracts adverse molecular protein signatures expected in IUGR kidneys. IUGR was induced by bilateral uterine vessel ligation or intrauterine stress through sham operation 3.5 days before term. Control (C) offspring were born after uncompromised pregnancy. On postnatal (P) days P2-P39, rats were fed control (n-3/n-6 PUFA ratio 1:20) or n-3 PUFA intervention diet (N3PUFA; ratio 1:1). Plasma parameters (P33), kidney cortex lipidomics and proteomics, as well as histology (P39) were studied. We found that the intervention diet tripled PL-DHA content (PC 40:6; P < 0.01) and lowered both PL-AA content (PC 38:4 and lyso-phosphatidylcholine 20:4; P < 0.05) and AA metabolites (HETEs, dihydroxyeicosatrienoic acids, and epoxyeicosatrienoic acids) to 25% in all offspring groups. After ligation, our network analysis of differentially expressed proteins identified an adverse molecular signature indicating inflammation and hypercoagulability. N3PUFA diet reversed 61 protein alterations (P < 0.05), thus mitigating adverse IUGR signatures. In conclusion, an elevated n-3/n-6 PUFA ratio in early diet strongly reduces proinflammatory PLs and mediators while increasing DHA-containing PLs regardless of prior intrauterine conditions. Counteracting a proinflammatory hypercoagulable protein signature in young adult IUGR individuals through early diet intervention may be a feasible strategy to prevent developmentally programmed kidney damage in later life.

Isoflurane stress induces region-specific glucocorticoid levels in neonatal mouse brain.

The profound programming effects of early life stress (ELS) on brain and behavior are thought to be primarily mediated by adrenal glucocorticoids (GCs). However, in mice, stressors are often administered between postnatal days 2 and 12 (PND2-12), during the stress hyporesponsive period (SHRP), when adrenal GC production is greatly reduced at baseline and in response to stressors. During the SHRP, specific brain regions produce GCs at baseline, but it is unknown if brain GC production increases in response to stressors. We treated mice at PND1 (pre-SHRP), PND5 (SHRP), PND9 (SHRP), and PND13 (post-SHRP) with an acute stressor (isoflurane anesthesia), vehicle control (oxygen), or neither (baseline). We measured a panel of progesterone and six GCs in the blood, hippocampus, cerebral cortex, and hypothalamus via liquid chromatography tandem mass spectrometry. At PND1, baseline corticosterone levels were high and did not increase in response to stress. At PND5, baseline corticosterone levels were very low, increases in brain corticosterone levels were greater than the increase in blood corticosterone levels, and stress had region-specific effects. At PND9, baseline corticosterone levels were low and increased similarly and moderately in response to stress. At PND13, blood corticosterone levels were higher than those at PND9, and corticosterone levels were higher in blood than in brain regions. These data illustrate the rapid and profound changes in stress physiology during neonatal development and suggest that neurosteroid production is a possible mechanism by which ELS has enduring effects on brain and behavior.

Exposure to a high-fat diet during intrauterine life and post-birth causes cardiac histomorphometric changes in rats: A systematic review.

Cardiac histomorphometric changes are conditions present as an adaptive response to increased cardiovascular demand, such as in obesity or the consumption of a high-fat diet. Epidemiologic studies show an increase in maternal obese individuals, with repercussions on offspring cardiovascular health. OBJECTIVE: The goal of this study was to systematically review studies that evaluated cardiac histomorphometric changes in rodents exposed to a high-fat diet. DATA SOURCE: PubMed, Embase, Science Direct, Web of Science and Lilacs. DATA EXTRACTION: Animal species, percentage of dietary fat, period and time of exposure and main cardiac change results were extracted. DATA ANALYSIS: A total of 1687 studies were found, and 20 met the inclusion criteria for this systematic review. A maternal high-fat diet was started 3 to 4 weeks before mating in most (70%) of the studies. Nutritional manipulation of offspring was initiated during pregnancy and maintained until the end of lactation in most (45%) of the studies. The fat percentage of high-fat diets ranged between 20% and 62%. The studies showed increases in cardiomyocytes, left ventricle size, and whole heart hypertrophy. Some studies showed increased thickness of the middle intima layer of the aorta and atherosclerosis. Studies that maintained a high-fat diet after the lactation period also showed an increase in cardiac hypertrophy. CONCLUSION: Maternal exposure to a hyperlipidic diet in the fetal stages of cardiac development causes cardiac hypertrophy in offspring. The high variation in the dietary fat and the difference in the time and period of exposure of the offspring to the high - fat diet suggest the high degree of sensitivity of the cardiac structure.

Neonatal D-fenfluramine treatment promotes long-term behavioral changes in adult mice.

Serotonin exerts a significant role in the mammalian central nervous system embryogenesis and brain ontogeny. Therefore, we investigate the effect of neonatal treatment of d-fenfluramine (d-FEN), a serotonin (5-HT) releaser, on the behavioral expression of adult male Swiss mice. For this purpose, we divided pregnant female Swiss mice into two groups (n = 6 each and ~35 g). Their offspring were treated with d-FEN (3 mg/kg, s.c.) from postnatal days (PND) 5 to 20. At PND 21, one male puppy of each litter was euthanized; the midbrain and the hippocampus were dissected for RNA analysis. At PND 70, the male offspring underwent a behavioral assessment in the open field, elevated plus-maze, light-dark box, tail suspension, and rotarod test. The programmed animals had a decrease in 5HT1a, serotonin transporter (SERT), and brain-derived neurotrophic factor (BDNF) expression in the mesencephalic raphe region. Alternatively, there was a reduction only in the tryptophan hydroxylase (TPH2) and BDNF expression in the hippocampus. In the light-dark box test, offspring of the treated group had higher latency to light and less time on the light side than the control. Also, it was observed less time of immobility in the tail suspension test. We also observed low motor skill learning in the rotarod test. These findings suggest that programming with d-FEN during the neonatal period alters a mesencephalic and hippocampal serotonergic system, promoting anxiety, antidepressant behavior, low coordination, and motor learning in adults.

Hippocampal mTOR Dysregulation and Morphological Changes in Male Rats after Fetal Growth Restriction.

Fetal growth restriction (FGR) has been linked to long-term neurocognitive impairment, especially in males. To determine possible underlying mechanisms, we examined hippocampal cellular composition and mTOR signaling of male rat FGR offspring during main brain growth and development (postnatal days (PND) 1 and 12). FGR was either induced by a low-protein diet throughout pregnancy, experimental placental insufficiency by bilateral uterine vessel ligation or intrauterine stress by "sham" operation. Offspring after unimpaired gestation served as common controls. Low-protein diet led to a reduced cell density in the molecular dentate gyrus subregion, while intrauterine surgical stress was associated with increased cell density in the cellular CA2 subregion. Experimental placental insufficiency caused increased mTOR activation on PND 1, whereas intrauterine stress led to mTOR activation on PND 1 and 12. To determine long-term effects, we additionally examined mTOR signaling and Tau phosphorylation, which is altered in neurodegenerative diseases, on PND 180, but did not find any changes among the experimental groups. Our findings suggest that hippocampal cellular proliferation and mTOR signaling are dysregulated in different ways depending on the cause of FGR. While a low-protein diet induced a decreased cell density, prenatal surgical stress caused hyperproliferation, possibly via increased mTOR signaling.

Maternal pregnancy weight or gestational weight gain and offspring's blood pressure: A systematic review.

AIMS: An increasing number of studies suggest that maternal weight parameters in pregnancy are associated with offspring's blood pressure (BP). The aim of this systematic review - following the updated Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement - was to assess and judge the evidence for an association between maternal pregnancy weight/body mass index (BMI) or gestational weight gain (GWG) with offspring's BP in later life. DATA SYNTHESIS: MEDLINE, EMBASE, Cochrane Library, CINAHL and Web of Science were searched without limits. Risk of bias was assessed using the "US National Heart, Lung and Blood Institute"-tool, and an evidence grade was allocated following the "World Cancer Research Fund" criteria. Of 7,124 publications retrieved, 16 studies (all cohort studies) were included in the systematic review. Overall data from 52,606 participants (0 years [newborns] to 32 years) were enclosed. Association between maternal pregnancy BMI and offspring's BP were analyzed in 2 (both "good-quality" rated) studies, without consistent results. GWG and offspring's BP was analyzed in 14 studies (2 "good-quality", 9 "fair-quality", 3 "poor-quality" rated). Of these, 3 "fair-quality" studies described significant positive results for systolic BP and significant results, but partly with varying directions of effect estimates for diastolic BP. Mean arterial pressure (MAP) was analyzed in 1 "poor-quality" congress paper. Overall, based on the small number of "good-quality"-rated studies and the inconsistency of effect direction, no firm conclusion can be drawn. CONCLUSION: Evidence for an association of maternal pregnancy weight determinants with offspring's BP was overall graded as "limited - no conclusion".

Brain-Restricted Inhibition of IL-6 Trans-Signaling Mildly Affects Metabolic Consequences of Maternal Obesity in Male Offspring.

Maternal obesity greatly affects next generations, elevating obesity risk in the offspring through perinatal programming and flawed maternal and newborn nutrition. The exact underlying mechanisms are poorly understood. Interleukin-6 (IL-6) mediates its effects through a membrane-bound receptor or by trans-signaling (tS), which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). As IL-6 tS mediates western-style diet (WSD) effects via chronic low-grade inflammation (LGI) and LGI is an important mediator in brain-adipose tissue communication, this study aims at determining the effects of maternal obesity in a transgenic mouse model of brain-restricted IL-6tS inhibition (GFAPsgp130) on offspring's short- and long-term body composition and epigonadal white adipose tissue (egWAT) metabolism. Female wild type (WT) or transgenic mice were fed either standard diet (SD) or WSD pregestationally, during gestation, and lactation. Male offspring received SD from postnatal day (P)21 to P56 and were metabolically challenged with WSD from P56 to P120. At P21, offspring from WT and transgenic dams that were fed WSD displayed increased body weight and egWAT mass, while glucose tolerance testing showed the strongest impairment in GFAPsgp130WSD offspring. Simultaneously, egWAT proteome reveals a characteristic egWAT expression pattern in offspring as a result of maternal conditions. IL-6tS inhibition in transgenic mice was in tendency associated with lower body weight in dams on SD and their respective offspring but blunted by the WSD. In conclusion, maternal nutrition affects offspring's body weight and egWAT metabolism predominantly independent of IL-6tS inhibition, emphasizing the importance of maternal and newborn nutrition for long-term offspring health.

The Relationship between Gestational Diabetes Metabolic Control and Fetal Autonomic Regulation, Movement and Birth Weight.

(1) Background: Maternal metabolic control in gestational diabetes is suggested to influence fetal autonomic control and movement activity, which may have fetal outcome implications. We aimed to analyze the relationship between maternal metabolic control, fetal autonomic heart rate regulation, activity and birth weight. (2) Methods: Prospective noninterventional longitudinal cohort monitoring study accompanying 19 patients with specialist clinical care for gestational diabetes. Monthly fetal magnetocardiography with electro-physiologically-based beat-to-beat heart rate recording for analysis of heart rate variability (HRV) and the 'fetal movement index' (FMI) was performed. Data were compared to 167 healthy pregnant women retrieved from our pre-existing study database. (3) Results: Fetal vagal tone was increased with gestational diabetes compared to controls, whereas sympathetic tone and FMI did not differ. Within the diabetic population, sympathetic activation was associated with higher maternal blood-glucose levels. Maternal blood-glucose levels correlated positively with birth weight z scores. FMI showed no correlation with birth weight but attenuated the positive correlation between maternal blood-glucose levels and birth weight. (4) Conclusion: Fetal autonomic control is altered by gestational diabetes and maternal blood-glucose level, even if metabolic adjustment and outcome is comparable to healthy controls.

Analysis of Both Lipid Metabolism and Endocannabinoid Signaling Reveals a New Role for Hypothalamic Astrocytes in Maternal Caloric Restriction-Induced Perinatal Programming.

Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers.

Maternal obesity is associated with an increased risk of hepatic metabolic dysfunction for both mother and offspring and targeted interventions to address this growing metabolic disease burden are urgently needed. This study investigates whether maternal exercise (ME) could reverse the detrimental effects of hepatic metabolic dysfunction in obese dams and their offspring while focusing on the AMP-activated protein kinase (AMPK), representing a key regulator of hepatic metabolism. In a mouse model of maternal western-style-diet (WSD)-induced obesity, we established an exercise intervention of voluntary wheel-running before and during pregnancy and analyzed its effects on hepatic energy metabolism during developmental organ programming. ME prevented WSD-induced hepatic steatosis in obese dams by alterations of key hepatic metabolic processes, including activation of hepatic ß-oxidation and inhibition of lipogenesis following increased AMPK and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α)-signaling. Offspring of exercised dams exhibited a comparable hepatic metabolic signature to their mothers with increased AMPK-PGC1α-activity and beneficial changes in hepatic lipid metabolism and were protected from WSD-induced adipose tissue accumulation and hepatic steatosis in later life. In conclusion, this study demonstrates that ME provides a promising strategy to improve the metabolic health of both obese mothers and their offspring and highlights AMPK as a potential metabolic target for therapeutic interventions.

Hyperosmolarity-induced vasopressin expression and intrinsic excitability of supraoptic neurons of adult offspring are changed by early maternal separation.

Adverse early life experiences can produce long-lasting changes in neurocircuits. The aim of this study was to investigate the programming effects of early maternal separation on the adult offspring vasopressin system. We hypothesized that subjecting adult rats to 4.5 h of daily maternal separation between postnatal days 1 - 21 will have altered hyperosmolarity-induced Avp expression and the response of supraoptic (SON) neurons to electrical and osmotic stimulation. We measured Avp mRNA and hn-RNA in the SON and in the paraventricular nucleus (PVN) by quantitative PCR, and assessed the intrinsic excitability of magnocellular SON neurons as well as their osmotic responses by the patch-clamp technique. In maternally-separated rats we found that basal and osmolarity-induced Avp mRNA gene expression was upregulated in the SON, whereas osmolarity-induced Avp hn-RNA gene expression was abolished. Similarly, in the PVN of maternally-separated rats the osmolarity-induced Avp mRNA gene expression was blunted. The supraoptic neurons of separated rats also had greater excitability than those of non-separated rats. Our results indicate that early maternal separation has long-term consequences on basal and hyperosmolarity-induced Avp hypothalamic expression as well as on the intrinsic excitability of magnocellular supraoptic neurons.