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1.
Gac Med Mex ; 160(1): 1-8, 2024.
Article in English | MEDLINE | ID: mdl-38753562

ABSTRACT

BACKGROUND: Protein interactions participate in many molecular mechanisms involved in cellular processes. The human TATA box binding protein (hTBP) interacts with Antennapedia (Antp) through its N-terminal region, specifically via its glutamine homopeptides. This PolyQ region acts as a binding site for other transcription factors under normal conditions, but when it expands, it generates spinocerebellar ataxia 17 (SCA17), whose protein aggregates in the brain prevent its correct functioning. OBJECTIVE: To determine whether the hTBP glutamine-rich region is involved in its interaction with homeoproteins and the role it plays in the formation of protein aggregates in SCA17. MATERIAL AND METHODS: We characterized hTBP interaction with other homeoproteins using BiFC, and modeled SCA17 in Drosophila melanogaster by targeting hTBPQ80 to the fly brain using UAS/GAL4. RESULTS: There was hTBP interaction with homeoproteins through its glutamine-rich region, and hTBP protein aggregates with expanded glutamines were found to affect the locomotor capacity of flies. CONCLUSIONS: The study of hTBP interactions opens the possibility for the search for new therapeutic strategies in neurodegenerative pathologies such as SCA17.


ANTECEDENTES: Las interacciones proteicas participan en una gran cantidad de mecanismos moleculares que rigen los procesos celulares. La proteína de unión a la caja TATA humana (hTBP) interacciona con Antennapedia (Antp) a través de su extremo N-terminal, específicamente a través de sus homopéptidos de glutaminas. Esta región PolyQ sirve como sitio de unión a factores de transcripción en condiciones normales, pero cuando se expande genera la ataxia espinal cerebelosa 17 (SCA17), cuyos agregados proteicos en el cerebro impiden su funcionamiento correcto. OBJETIVO: Determinar si la región rica en glutaminas de hTBP interviene en su interacción con homeoproteínas y el papel que tiene en la formación de agregados proteicos en SCA17. MATERIAL Y MÉTODOS: Se caracterizó la interacción de hTBP con otras homeoproteínas usando BiFC y se modeló SCA17 en Drosophila melanogaster dirigiendo hTBPQ80 al cerebro de las moscas usando UAS/GAL4. RESULTADOS: Existió interacción de hTBP con homeoproteínas a través de su región rica en glutaminas. Los agregados proteicos de hTBP con las glutaminas expandidas afectaron la capacidad locomotriz de las moscas. CONCLUSIONES: El estudio de las interacciones de hTBP abre la posibilidad para la búsqueda de nuevas estrategias terapéuticas en patologías neurodegenerativas como SCA17.


Subject(s)
Disease Models, Animal , Drosophila melanogaster , Spinocerebellar Ataxias , TATA-Box Binding Protein , Animals , Drosophila melanogaster/metabolism , Spinocerebellar Ataxias/metabolism , Spinocerebellar Ataxias/genetics , TATA-Box Binding Protein/metabolism , TATA-Box Binding Protein/genetics , Humans , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Glutamine/metabolism , Protein Aggregates/physiology , Peptides/metabolism , Brain/metabolism
2.
Gac. méd. Méx ; 160(1): 1-9, ene.-feb. 2024. graf
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1557797

ABSTRACT

Resumen Antecedentes: Las interacciones proteicas participan en una gran cantidad de mecanismos moleculares que rigen los procesos celulares. La proteína de unión a la caja TATA humana (hTBP) interacciona con Antennapedia (Antp) a través de su extremo N-terminal, específicamente a través de sus homopéptidos de glutaminas. Esta región PolyQ sirve como sitio de unión a factores de transcripción en condiciones normales, pero cuando se expande genera la ataxia espinal cerebelosa 17 (SCA17), cuyos agregados proteicos en el cerebro impiden su funcionamiento correcto. Objetivo: Determinar si la región rica en glutaminas de hTBP interviene en su interacción con homeoproteínas y el papel que tiene en la formación de agregados proteicos en SCA17. Material y métodos: Se caracterizó la interacción de hTBP con otras homeoproteínas usando BiFC y se modeló SCA17 en Drosophila melanogaster dirigiendo hTBPQ80 al cerebro de las moscas usando UAS/GAL4. Resultados: Existió interacción de hTBP con homeoproteínas a través de su región rica en glutaminas. Los agregados proteicos de hTBP con las glutaminas expandidas afectaron la capacidad locomotriz de las moscas. Conclusiones: El estudio de las interacciones de hTBP abre la posibilidad para la búsqueda de nuevas estrategias terapéuticas en patologías neurodegenerativas como SCA17.


Abstract Background: Protein interactions participate in many molecular mechanisms involved in cellular processes. The human TATA box binding protein (hTBP) interacts with Antennapedia (Antp) through its N-terminal region, specifically via its glutamine homopeptides. This PolyQ region acts as a binding site for other transcription factors under normal conditions, but when it expands, it generates spinocerebellar ataxia 17 (SCA17), whose protein aggregates in the brain prevent its correct functioning. Objective: To determine whether the hTBP glutamine-rich region is involved in its interaction with homeoproteins and the role it plays in the formation of protein aggregates in SCA17. Material and methods: We characterized hTBP interaction with other homeoproteins using BiFC, and modeled SCA17 in Drosophila melanogaster by targeting hTBPQ80 to the fly brain using UAS/GAL4. Results: There was hTBP interaction with homeoproteins through its glutamine-rich region, and hTBP protein aggregates with expanded glutamines were found to affect the locomotor capacity of flies. Conclusions: The study of hTBP interactions opens the possibility for the search for new therapeutic strategies in neurodegenerative pathologies such as SCA17.

3.
Mol Neurobiol ; 2024 Jan 26.
Article in English | MEDLINE | ID: mdl-38277116

ABSTRACT

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that involves functional and structural defects in selective central nervous system (CNS) regions, harming the individual capability to process and respond to external stimuli, including impaired verbal and non-verbal communications. Etiological causes of ASD have not been fully clarified; however, prenatal activation of the innate immune system by external stimuli might infiltrate peripheral immune cells into the fetal CNS and activate cytokine secretion by microglia and astrocytes. For instance, genomic and postmortem histological analysis has identified proinflammatory gene signatures, microglia-related expressed genes, and neuroinflammatory markers in the brain during ASD diagnosis. Active neuroinflammation might also occur during the developmental stage, promoting the establishment of a defective brain connectome and increasing susceptibility to ASD after birth. While still under investigation, we tested the hypothesis whether the monocyte chemoattractant protein-1 (MCP-1) signaling is prenatally programmed to favor peripheral immune cell infiltration and activate microglia into the fetal CNS, setting susceptibility to autism-like behavior. In this review, we will comprehensively provide the current understanding of the prenatal activation of MCP-1 signaling by external stimuli during the developmental stage as a new selective node to promote neuroinflammation, brain structural alterations, and behavioral defects associated to ASD diagnosis.

4.
Breastfeed Med ; 18(12): 934-942, 2023 12.
Article in English | MEDLINE | ID: mdl-38100442

ABSTRACT

Background: Breast milk (BM) is a nutritive fluid that is rich in bioactive components such as hormones and cytokines that can shape the newborn's feeding habits and program the newborn's immature immune system. BM components can change under different scenarios that include maternal body mass index (BMI) and premature birth. This study aimed to study the interaction of premature status or maternal obesity on the hormonal and cytokine profile in BM according to the sex of the offspring. Materials and Methods: We recruited 31 women with preterm births from the Centro de Alta Especialidad Dr. Rafael Lucio in Mexico. Luminex multiplexing assay was used for quantifying cytokine profile of monocyte chemoattractant protein-1, tumor necrosis factor (TNF)-α, interferon-γ, interleukin (IL)1-ß, IL-2, IL-4, IL-6, IL-7, and hormones insulin, ghrelin, leptin, and glucagon in mature BM samples. Biological modeling was performed to predict the interaction between cytokines and hormones, maternal BMI status, infant birth sex, parity, and gestational age. Results: BM multiplex analysis showed positive correlations for TNF-α and increasing prematurity and for higher maternal BMI and IL-2, IL-4, and IL-6 cytokines. Multiple regression models identified an interaction between maternal BMI and gestational weeks in male infants that is associated to TNF-α accumulation in BM. Biological modeling predicts that preterm delivery in mothers with obesity modulates TNF- α levels in mature BM of women with male offspring. Conclusion: Prematurity and obesity modify BM's immune profile. TNF- α expression increases as prematurity increases, and maternal BMI correlates positively with increases in IL-2, IL-6, and IL-4. Our multiple regression model also shows that maternal BMI and gestational weeks in male infants predict TNF-α.


Subject(s)
Milk, Human , Premature Birth , Female , Humans , Infant , Infant, Newborn , Male , Pregnancy , Breast Feeding , Cytokines , Interleukin-2 , Interleukin-4 , Interleukin-6/analysis , Milk, Human/chemistry , Obesity , Tumor Necrosis Factor-alpha/analysis
5.
Environ Sci Pollut Res Int ; 30(42): 95139-95154, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37597149

ABSTRACT

Industrial activities provide a modern human lifestyle with advances and comforts in every field. However, such scenario has brought several negative issues. Persistent organic pollutants (POPs) and a growing plastic usage together with the degradation byproducts, namely microplastics (MPs), are current environmental problems present in every ecosystem, disturbing all forms of life. POPs and MPs are also found in human consumption products including animal and vegetal derivatives, human milk substitutes, and in human breast milk. To date, it is currently unknown what are the effects of MPs and POPs when ingested during the first and most important stage for health programming of the offspring, the first 1000 days of life. Here, we add epidemiological and clinical evidence supporting major sources of POPs and MPs in the ecosystem; and we will precisely describe the effect of POP and MP accumulation in animal- or plant-based infant formulas and human breast milk, modulating health outcomes in the newborn. This review provides a rational to incentive the POP and MP identification in human breast milk and human milk substitutes for avoiding susceptibility to negative health outcomes for the newborn.


Subject(s)
Environmental Pollutants , Milk Substitutes , Animals , Female , Infant , Infant, Newborn , Humans , Persistent Organic Pollutants , Microplastics , Plastics , Ecosystem , Milk, Human
6.
Nutr Res ; 107: 37-47, 2022 11.
Article in English | MEDLINE | ID: mdl-36174387

ABSTRACT

Maternal overnutrition during pregnancy leads to metabolic and immune alterations, including obesity, hyperphagia, and central and peripheral inflammation in offspring. Exposure to high-energy diets during pregnancy primes ghrelin sensitivity to overfeeding in the offspring at early stages of life. Overfeeding has also been partially related to the early stages of chronic stress. We hypothesized that maternal programming sensitizes ghrelin-induced overfeeding following a chronic stress schedule in the offspring. We used a nutritional programming model exposing female Wistar rats to a cafeteria (CAF) or control diet from prepregnancy to weaning. Male offspring were injected with ghrelin and then subjected to a chronic immobilization stress (CIS) schedule, after which food intake was determined. Hypothalamic and plasma accumulation of cytokines and cortisol were evaluated using BioPlex analysis and enzyme-linked immunosorbent assay, respectively. We found that rats exposed to the CAF diet exhibited overfeeding after fasting and peripheral ghrelin administration, which was exacerbated in rats exposed to chronic stress. Offspring exposed to the CAF diet accumulated pro-inflammatory interleukin-6 (IL-6), interferon-γ, and monocyte chemoattractant protein-1 cytokines in plasma, and IL-6 cytokine in the hypothalamus. Ghrelin-sensitive overfeeding in rats exposed to CAF diet + CIS display increased cortisol levels and decreased IL-6 accumulation in plasma. Together, our results suggest that maternal nutritional programming primes susceptibility to ghrelin response for overfeeding after a CIS schedule that mirrors plasma cortisol accumulation in male offspring.


Subject(s)
Ghrelin , Prenatal Exposure Delayed Effects , Animals , Female , Male , Pregnancy , Rats , Diet , Hydrocortisone , Interleukin-6 , Maternal Nutritional Physiological Phenomena , Prenatal Exposure Delayed Effects/metabolism , Rats, Wistar , Stress, Physiological
7.
Neuroreport ; 33(12): 495-503, 2022 08 02.
Article in English | MEDLINE | ID: mdl-35776941

ABSTRACT

OBJECTIVE: This study aimed to characterize the molecular immune networks and microglia reactivity in the nucleus accumbens (NAc) shell affected by fetal nutritional programming leading to addiction-like behavior in the offspring of Wistar rats. Fetal nutritional programming by energy-dense foods leads to addiction-like behavior in the offspring. Exposure to energy-dense foods also activates systemic and central inflammation in the offspring. METHODS: Females Wistar rats were exposed to cafeteria (CAF) diet or control diet for 9 weeks (prepregnancy, pregnancy and lactation), and male offspring at 2 months of age were diagnosed with food addiction-like behavior using operant conditioning. Global microarray analysis, RTqPCR, proinflammatory plasma profile and microglia immunostaining were performed in the NAc shell of male rats. SIM-A9 microglia cells were stimulated with IFN-α and palmitic acid, and microglia activation and phagocytosis were determined by RTqPCR and incubation of green-fluorescent latex beads, respectively. RESULTS: Microarray analysis in the NAc shell of the male offspring exposed to CAF during development and diagnosed with addiction-like behavior showed increasing in the type I interferon-inducible gene, Ift1 , gene network. Genomic and cellular characterization also confirmed microglia hyperreactivity and upregulation of the Ifit1 in the NAc shell of animals with addiction-like behavior. In-vitro models demonstrated that microglia do respond to IFN-α promoting a time-dependent genomic expression of Ift1, IL-1ß and IL-6 followed by increased phagocytosis. CONCLUSION: Prenatal exposure to energy-dense foods primes the IFN type I signaling and microglia complexity in the NAc shell of rats diagnosed with food addiction-like behavior.


Subject(s)
Food Addiction , Interferon Type I , Pregnancy , Female , Rats , Animals , Male , Nucleus Accumbens/metabolism , Microglia/metabolism , Rats, Wistar , Food Addiction/metabolism , Interferon Type I/metabolism , Diet
8.
Neurochem Res ; 47(10): 3093-3103, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35767136

ABSTRACT

Maternal nutritional programming by energy-dense foods leads to the transgenerational heritance of addiction-like behavior. Exposure to energy-dense foods also activates systemic and central inflammation in the offspring. This study aimed to characterize pro- and anti-inflammatory cytokine profiles in blood and their correlation to the transgenerational heritance of the addiction-like behavior in rats. F1 offspring of male Wistar diagnosed with addiction-like behavior were mated with virgin females to generate the F2 and the F3 offspring, respectively. Diagnosis of addiction-like behavior was performed by the operant training schedule (FR1, FR5 and PR) and pro- and anti-inflammatory cytokine profiles in blood were measured by multiplex platform. Multiple linear models between behavior, fetal programming by diet and pro- and anti-inflammatory cytokine profiles were performed. We found that the addiction-like behavior found in the F1 male offspring exposed to energy-dense food (cafeteria, CAF) diet during fetal programing is transgenerational inherited to the F2 and F3 generations. Blood from addiction-like behavior subjects of F2 and F3 generations exposed to CAF diet during maternal programming showed decrease in the anti-inflammatory IL-10 in the plasma. Conversely, decreased levels of the pro-inflammatory MCP-1 was identified in non-addiction-like subjects. No changes were found in plasmatic TNF-α levels in the F2 and F3 offspring of non-addiction-like and addiction-like subjects. Finally, biological modeling between IL-10 or MCP-1 plasma levels and prenatal diet exposure on operant training responses confirmed an association of decreased IL-10 levels on addiction-like behavior in the F2 and F3 generations. Globally, we identified decreased anti-inflammatory IL-10 cytokine in the blood of F2 and F3 offspring subjects diagnosed with addiction-like behavior for food rewards.


Subject(s)
Food Addiction , Prenatal Exposure Delayed Effects , Animals , Anti-Inflammatory Agents , Conditioning, Operant , Female , Humans , Interleukin-10 , Male , Pregnancy , Rats , Rats, Wistar
9.
Neuroimage ; 252: 119039, 2022 05 15.
Article in English | MEDLINE | ID: mdl-35227858

ABSTRACT

Ageing displays a low-grade pro-inflammatory profile in blood and the brain. Accumulation of pro-inflammatory cytokines, microglia activation and volumetric changes in the brain correlate with cognitive decline in ageing models. However, the interplay between them is not totally understood. Here, we aimed to globally identify an age-dependent pro-inflammatory profile and microglia morphological plasticity that favors major volume changes in the brain associated with cognitive decline. Cluster analysis of behavioral data obtained from 2-,12- and 20-month-old male C57BL/6 mice revealed age-dependent cognitive decline after the Y-maze, Barnes maze, object recognition (NORT) and object location tests (OLT). Global magnetic resonance imageing (MRI) analysis by deformation-based morphometry (DBM) in the brain identified a volume increase in the fornix and a decrease in the left medial entorhinal cortex (MEntC) during ageing. Notably, the fornix shows an increase in the accumulation of pro-inflammatory cytokines, whereas the left MEntC displays a decrease. Morphological assessment of microglia also confirms an active and dystrophic phenotype in the fornix and a surveillance phenotype in the left MEntC. Finally, biological modeling revealed that age-related volume increase in the fornix was associated with dystrophic microglia and cognitive impairment, as evidenced by failure on tasks examining memory of object location and novelty. Our results propose that the morphological plasticity of microglia might contribute to volumetric changes in brain regions associated with cognitive decline during physiological ageing.


Subject(s)
Cognitive Dysfunction , Microglia , Aging , Animals , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/pathology , Cytokines , Humans , Male , Memory Disorders/diagnostic imaging , Memory Disorders/pathology , Mice , Mice, Inbred C57BL , Spatial Memory/physiology
10.
J Med Food ; 24(8): 833-840, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33570459

ABSTRACT

Maternal high-sweetener diet, such as sucrose, has been associated with an increased risk of metabolic and cognitive-related diseases in the offspring. This study was performed to determine the effect of maternal sweetener intake during gestation and lactation on learning and memory in adult female offspring rats. Twenty-eight female pups from dams fed standard diet (Control-C, n = 10), high-sucrose diet (HS-C, n = 6), and high-honey diet (Ho-C, n = 12) were fed standard diet after weaning and body weight and food intake were recorded once a week for 19 weeks. Learning and memory tests were conducted at week 14 (Y-maze) and 18 (Barnes maze). We found that birth weight of Control-C group was greater than the Ho-C (P < .001). Blood glucose levels of the HS-C group were significantly higher than the Control-C and Ho-C groups. Control-C pups recognized the novel arm of the Y-maze compared with HS-C and Ho-C groups (P < .01). Also, offspring of the HS-C group showed deficient performance in the Barnes test when compared with the Control-C and Ho-C groups (P < .05). These results suggest that dams fed a high-sucrose diet during gestation and lactation favor high-glucose levels and deficient long-term memory performance in adult female offspring rats.


Subject(s)
Maternal Nutritional Physiological Phenomena , Prenatal Exposure Delayed Effects , Animals , Body Weight , Diet , Female , Humans , Lactation , Pregnancy , Rats , Sweetening Agents , Weaning
11.
J Neurochem ; 156(4): 415-434, 2021 02.
Article in English | MEDLINE | ID: mdl-32902852

ABSTRACT

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease which involves functional and structural defects in selective central nervous system (CNS) regions that harm function and individual ability to process and respond to external stimuli. Individuals with ASD spend less time engaging in social interaction compared to non-affected subjects. Studies employing structural and functional magnetic resonance imaging reported morphological and functional abnormalities in the connectivity of the mesocorticolimbic reward pathway between the nucleus accumbens and the ventral tegmental area (VTA) in response to social stimuli, as well as diminished medial prefrontal cortex in response to visual cues, whereas stronger reward system responses for the non-social realm (e.g., video games) than social rewards (e.g., approval), associated with caudate nucleus responsiveness in ASD children. Defects in the mesocorticolimbic reward pathway have been modulated in transgenic murine models using D2 dopamine receptor heterozygous (D2+/-) or dopamine transporter knockout mice, which exhibit sociability deficits and repetitive behaviors observed in ASD phenotypes. Notably, the mesocorticolimbic reward pathway is modulated by systemic and central inflammation, such as primed microglia, which occurs during obesity or maternal overnutrition. Therefore, we propose that a positive energy balance during obesity/maternal overnutrition coordinates a systemic and central inflammatory crosstalk that modulates the dopaminergic neurotransmission in selective brain areas of the mesocorticolimbic reward pathway. Here, we will describe how obesity/maternal overnutrition may prime microglia, causing abnormalities in dopamine neurotransmission of the mesocorticolimbic reward pathway, postulating a possible immune role in the development of ASD.


Subject(s)
Autism Spectrum Disorder/metabolism , Limbic System/metabolism , Microglia/metabolism , Nerve Net/metabolism , Obesity/metabolism , Prefrontal Cortex/metabolism , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/pathology , Humans , Limbic System/pathology , Microglia/pathology , Nerve Net/pathology , Obesity/epidemiology , Obesity/pathology , Prefrontal Cortex/pathology
12.
Front Pediatr ; 9: 746437, 2021.
Article in English | MEDLINE | ID: mdl-35071124

ABSTRACT

Background: There is increasing evidence that gut microbiota in offspring is derived in part from maternal environment such as diet. Thus, sweeteners intake including caloric or non-caloric during perinatal period can induce gut dysbiosis and program the offspring to develop cognitive problems later in life. Objective: To determine the effect of maternal high-sweeteners intake during gestation and lactation on gut microbiota shifts in adult male offspring rats and the impact on cognitive dysfunction. Methods: Thirty-four male pups from dams fed standard diet (Control-C, n = 10), high-sucrose diet (HS-C, n = 11), high-honey diet (Ho-C, n = 8), and high-stevia diet (HSt-C, n = 5) were fed standard diet after weaning, and body weight and food intake were recorded once a week for 26 weeks. Learning and memory tests were performed at week 23 of life using the Barnes maze. Fecal samples from the breastfeeding and adulthood periods were collected and analyzed by sequencing the 16S rRNA V3-V4 region of gut microbiota. Results: Maternal high-sucrose and stevia diets programmed the male offspring, and changes in microbial diversity by Shannon index were observed after weaning (p < 0.01). Furthermore, maternal high-stevia diet programming lasted into adulthood. The increase of Firmicutes abundance and the decrease in phylum Bacteroidetes were significant in HS-C and HSt-C groups. This led to an increase in the Firmicutes/Bacteroidetes index, although only in HS-C group was statistically significant (p < 0.05). Of note, the downstream gram-negative Bacteroidales and the upregulation of the gram-positive Clostridiales abundance contribute to cognitive dysfunction. Conclusion: These results suggest that dams fed a high-sucrose and stevia diets during gestation and lactation favor a deficient memory performance in adult male offspring rats through shifts gut microbiota diversity and relative abundance at several taxa.

13.
Front Neurosci ; 14: 452, 2020.
Article in English | MEDLINE | ID: mdl-32581665

ABSTRACT

Fetal programming by hypercaloric intake leads to food addiction-like behavior and brain pro-inflammatory gene expression in offspring. The role of methylome modulation during programming on central immune activation and addiction-like behavior has not been characterized. We employed a nutritional programming model exposing female Wistar rats to chow diet, cafeteria (CAF), or CAF-methyl donor's diet from pre-pregnancy to weaning. Addiction-like behavior in offspring was characterized by the operant training response using Skinner boxes. Food intake in offspring was determined after fasting-refeeding schedule and subcutaneous injection of ghrelin. Genome-wide DNA methylation in the nucleus accumbens (NAc) shell was performed by fluorescence polarization, and brain immune activation was evaluated using real-time PCR for pro-inflammatory cytokines (IL-1ß, TNF-1α, and IL-6). Molecular effects of methyl modulators [S-adenosylmethionine (SAM) or 5-azatidine (5-AZA)] on pro-inflammatory cytokine expression and phagocytosis were identified in the cultures of immortalized SIM-A9 microglia cells following palmitic acid (100 µM) or LPS (100 nM) stimulation for 6 or 24 h. Our results show that fetal programming by CAF exposure increases the number of offspring subjects and reinforcers under the operant training response schedule, which correlates with an increase in the NAc shell global methylation. Notably, methyl donor's diet selectively decreases lever-pressing responses for reinforcers and unexpectedly decreases the NAc shell global methylation. Also, programmed offspring by CAF diet shows a selective IL-6 gene expression in the NAc shell, which is reverted to control values by methyl diet exposure. In vitro analysis identified that LPS and palmitic acid activate IL-1ß, TNF-1α, and IL-6 gene expression, which is repressed by the methyl donor SAM. Finally, methylation actively represses phagocytosis activity of SIM-A9 microglia cells induced by LPS and palmitic acid stimulation. Our in vivo and in vitro data suggest that fetal programming by methyl donors actively decreases addiction-like behavior to palatable food in the offspring, which correlates with a decrease in NAc shell methylome, expression of pro-inflammatory cytokine genes, and activity of phagocytic microglia. These results support the role of fetal programming in brain methylome on immune activation and food addiction-like behavior in the offspring.

14.
Front Neurosci ; 14: 13, 2020.
Article in English | MEDLINE | ID: mdl-32116490

ABSTRACT

Maternal overnutrition modulates body weight, development of metabolic failure and, potentially, neurodegenerative susceptibility in the offspring. Overnutrition sets a chronic pro-inflammatory profile that integrates peripheral and central immune activation nodes, damaging neuronal physiology and survival. Innate immune cells exposed to hypercaloric diets might experience trained immunity. Here, we address the role of maternal overnutrition as a trigger for central and peripheral immune training and its contribution to neurodegeneration and the molecular nodes implicated in the Nod-like receptor protein 3 (NLRP3) inflammasome pathway leading to immune training. We propose that maternal overnutrition leads to peripheral or central immune training that favor neurodegenerative susceptibility in the offspring.

15.
Nutrients ; 11(6)2019 May 31.
Article in English | MEDLINE | ID: mdl-31159189

ABSTRACT

Maternal overnutrition during pregnancy leads to metabolic alterations, including obesity, hyperphagia, and inflammation in the offspring. Nutritional priming of central inflammation and its role in ghrelin sensitivity during fed and fasted states have not been analyzed. The current study aims to identify the effect of maternal programming on microglia activation and ghrelin-induced activation of hypothalamic neurons leading to food intake response. We employed a nutritional programming model exposing female Wistar rats to a cafeteria diet (CAF) from pre-pregnancy to weaning. Food intake in male offspring was determined daily after fasting and subcutaneous injection of ghrelin. Hypothalamic ghrelin sensitivity and microglia activation was evaluated using immunodetection for Iba-1 and c-Fos markers, and Western blot for TBK1 signaling. Release of TNF-alpha, IL-6, and IL-1ß after stimulation with palmitic, oleic, linoleic acid, or C6 ceramide in primary microglia culture were quantified using ELISA. We found that programmed offspring by CAF diet exhibits overfeeding after fasting and peripheral ghrelin administration, which correlates with an increase in the hypothalamic Iba-1 microglia marker and c-Fos cell activation. Additionally, in contrast to oleic, linoleic, or C6 ceramide stimulation in primary microglia culture, stimulation with palmitic acid for 24 h promotes TNF-alpha, IL-6, and IL-1ß release and TBK1 activation. Notably, intracerebroventricular (i.c.v.) palmitic acid or LPS inoculation for five days promotes daily increase in food intake and food consumption after ghrelin administration. Finally, we found that i.c.v. palmitic acid substantially activates hypothalamic Iba-1 microglia marker and c-Fos. Together, our results suggest that maternal nutritional programing primes ghrelin sensitivity and microglia activation, which potentially might mirror hypothalamic administration of the saturated palmitic acid.


Subject(s)
Ghrelin/pharmacology , Maternal Nutritional Physiological Phenomena , Microglia/physiology , Overnutrition , Signal Transduction/drug effects , Animals , Blood Glucose , Eating , Female , Ghrelin/metabolism , Hypothalamus/cytology , Hypothalamus/drug effects , Insulin Resistance , Male , Neurons/drug effects , Pregnancy , Rats , Rats, Wistar , Signal Transduction/physiology
16.
Biomed Res Int ; 2018: 8061389, 2018.
Article in English | MEDLINE | ID: mdl-30027100

ABSTRACT

Obesity or maternal overnutrition during pregnancy and lactation might have long-term consequences in offspring health. Fetal programming is characterized by adaptive responses to specific environmental conditions during early life stages. Programming alters gene expression through epigenetic modifications leading to a transgenerational effect of behavioral phenotypes in the offspring. Maternal intake of hypercaloric diets during fetal development programs aberrant behaviors resembling addiction in offspring. Programming by hypercaloric surplus sets a gene expression pattern modulating axonal pruning, synaptic signaling, and synaptic plasticity in selective regions of the reward system. Likewise, fetal programming can promote an inflammatory phenotype in peripheral and central sites through different cell types such as microglia and T and B cells, which contribute to disrupted energy sensing and behavioral pathways. The molecular mechanism that regulates the central and peripheral immune cross-talk during fetal programming and its relevance on offspring's addictive behavior susceptibility is still unclear. Here, we review the most relevant scientific reports about the impact of hypercaloric nutritional fetal programming on central and peripheral inflammation and its effects on addictive behavior of the offspring.


Subject(s)
Behavior, Addictive , Maternal Nutritional Physiological Phenomena , Overnutrition , Prenatal Exposure Delayed Effects , Animals , Female , Fetal Development , Inflammation , Obesity , Pregnancy
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