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BACKGROUND: Pre-pregnancy overweight and obesity promote deleterious health impacts on both mothers during pregnancy and the offspring. Significant changes in the maternal peripheral blood mononuclear cells (PBMCs) gene expression due to obesity are well-known. However, the impact of pre-pregnancy overweight on immune cell gene expression during pregnancy and its association with maternal and infant outcomes is not well explored. METHODS: Blood samples were collected from healthy normal weight (NW, pre-pregnancy BMI 18.5-24.9) or overweight (OW, pre-pregnancy BMI 25-29.9) 2nd parity pregnant women at 12, 24 and 36 weeks of pregnancy. PBMCs were isolated from the blood and subjected to mRNA sequencing. Maternal and infant microbiota were analyzed by 16S rRNA gene sequencing. Integrative multi-omics data analysis was performed to evaluate the association of gene expression with maternal diet, gut microbiota, milk composition, and infant gut microbiota. RESULTS: Gene expression analysis revealed that 453 genes were differentially expressed in the OW women compared to NW women at 12 weeks of pregnancy, out of which 354 were upregulated and 99 were downregulated. Several up-regulated genes in the OW group were enriched in inflammatory, chemokine-mediated signaling and regulation of interleukin-8 production-related pathways. At 36 weeks of pregnancy healthy eating index score was positively associated with several genes that include, DTD1, ELOC, GALNT8, ITGA6-AS1, KRT17P2, NPW, POT1-AS1 and RPL26. In addition, at 36 weeks of pregnancy, genes involved in adipocyte functions, such as NG2 and SMTNL1, were negatively correlated to human milk 2'FL and total fucosylated oligosaccharides content collected at 1 month postnatally. Furthermore, infant Akkermansia was positively associated with maternal PBMC anti-inflammatory genes that include CPS1 and RAB7B, at 12 and 36 weeks of pregnancy. CONCLUSIONS: These findings suggest that prepregnancy overweight impacts the immune cell gene expression profile, particularly at 12 weeks of pregnancy. Furthermore, deciphering the complex association of PBMC's gene expression levels with maternal gut microbiome and milk composition and infant gut microbiome may aid in developing strategies to mitigate obesity-mediated effects.
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BACKGROUND/AIM: This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver inflammatory markers in obese C57BL/6J mice. MATERIALS AND METHODS: Forty male C57BL/6J mice were fed a high-fat diet (HFD) and assigned into four groups in a 2 (no statin vs. 120 mg statin/kg diet)×2 (no TT vs. 400 mg TT/kg diet) factorial design for 14 weeks. RESULTS: Statin and TT improved glucose tolerance only when each was given alone, and only statin supplementation decreased insulin resistance. Consistently, only statin supplementation decreased serum insulin levels and HOMA-IR. Pancreatic insulin was also increased with statin treatment. Statin and TT, alone or in combination, reduced the levels of serum IL-6, but only TT attenuated the increased serum leptin levels induced by a HFD. Statin supplementation increased bone area/total area and connectivity density at LV-4, while TT supplementation increased bone area/total area and trabecular number, but decreased trabecular separation at the distal femur. Statin supplementation, but not TT, reduced hepatic inflammatory cytokine gene expression. Neither TT supplementation nor statin supplementation statistically altered microbiome species evenness or richness. However, they altered the relative abundance of certain microbiome species. Most notably, both TT and statin supplementation increased the relative abundance of Lachnospiraceae UCG-006. CONCLUSION: TT and statin collectively benefit bone microstructure, glucose homeostasis, and microbial ecology in obese mice. Such changes may be, in part, associated with suppression of inflammation in the host.
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Osso e Ossos , Dieta Hiperlipídica , Suplementos Nutricionais , Microbioma Gastrointestinal , Homeostase , Inibidores de Hidroximetilglutaril-CoA Redutases , Obesidade , Tocotrienóis , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Tocotrienóis/farmacologia , Tocotrienóis/administração & dosagem , Camundongos , Homeostase/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Masculino , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Dieta Hiperlipídica/efeitos adversos , Bixaceae/química , Camundongos Obesos , Extratos Vegetais/farmacologia , Extratos Vegetais/administração & dosagem , Glucose/metabolismo , Camundongos Endogâmicos C57BL , Resistência à Insulina , Glicemia , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Biomarcadores , CarotenoidesRESUMO
The placenta is crucial for fetal development, is affected by PFAS toxicity, and evidence is accumulating that gestational PFAS perturb the epigenetic activity of the placenta. Gestational PFAS exposure is can adversely affect offspring, yet individual and cumulative impacts of PFAS on the placental epigenome remain underexplored. Here, we conducted an epigenome-wide association study (EWAS) to examine the relationships between placental PFAS levels and DNA methylation in a cohort of mother-infant dyads in Arkansas. We measured 17 PFAS in human placental tissues and quantified placental DNA methylation levels via the Illumina EPIC Microarray. We tested for differential DNA methylation with individual PFAS, and with mixtures of multiple PFAS. Our results demonstrated that numerous epigenetic loci were perturbed by PFAS, with PFHxS exhibiting the most abundant effects. Mixture analyses suggested cumulative effects of PFOA and PFOS, while PFHxS may act more independently. We additionally explored whether sex-specific effects may be present and concluded that future large studies should explicitly test for sex-specific effects. The genes that are annotated to our PFAS-associated epigenetic loci are primarily involved in growth processes and cardiometabolic health, while some genes are involved in neurodevelopment. These findings shed light on how prenatal PFAS exposures affect birth outcomes and children's health, emphasizing the importance of understanding PFAS mechanisms in the in-utero environment.
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Background and aims: Spinal cord injury (SCI) affects roughly 300,000 Americans with 17,000 new cases added annually. In addition to paralysis, 60% of people with SCI develop neurogenic bowel (NB), a syndrome characterized by slow colonic transit, constipation, and chronic abdominal pain. The knowledge gap surrounding NB mechanisms after SCI means that interventions are primarily symptom-focused and largely ineffective. The goal of the present studies was to identify mechanism(s) that initiate and maintain NB after SCI as a critical first step in the development of evidence-based, novel therapeutic treatment options. Methods: Following spinal contusion injury at T9, we observed alterations in bowel structure and function reflecting key clinical features of NB. We then leveraged tissue-specific whole transcriptome analyses (RNAseq) and fecal 16S rRNA amplicon sequencing in combination with histological, molecular, and functional (Ca2+ imaging) approaches to identify potential mechanism(s) underlying the generation of the NB phenotype. Results: In agreement with prior reports focused on SCI-induced changes in the skin, we observed a rapid and persistent increase in expression of calcitonin gene-related peptide (CGRP) expression in the colon. This is suggestive of a neurogenic inflammation-like process engaged by antidromic activity of below-level primary afferents following SCI. CGRP has been shown to disrupt colon homeostasis and negatively affect peristalsis and colon function. As predicted, contusion SCI resulted in increased colonic transit time, expansion of lymphatic nodules, colonic structural and genomic damage, and disruption of the inner, sterile intestinal mucus layer corresponding to increased CGRP expression in the colon. Gut microbiome colonization significantly shifted over 28 days leading to the increase in Anaeroplasma, a pathogenic, gram-negative microbe. Moreover, colon specific vagal afferents and enteric neurons were hyperresponsive after SCI to different agonists including fecal supernatants. Conclusions: Our data suggest that SCI results in overexpression of colonic CGRP which could alter colon structure and function. Neurogenic inflammatory-like processes and gut microbiome dysbiosis can also sensitize vagal afferents, providing a mechanism for visceral pain despite the loss of normal sensation post-SCI. These data may shed light on novel therapeutic interventions targeting this process to prevent NB development in patients.
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BACKGROUND: Human milk oligosaccharides have been shown to relate to the infant gut microbiome. However, the impact of other human milk components on infant gut bacterial colonization remains unexplored. OBJECTIVES: Our cross-sectional analysis aimed to investigate associations between human milk components (energy, macronutrients, free amino acids, inflammatory markers, and hormones) and infant gut microbiome diversity and composition (phylum, family, and genus) at 6 mo of age. METHODS: Human milk and infant stool samples were collected at 6 mo postpartum. The infant gut microbiome was profiled using 16S rRNA sequencing. Linear regression models were performed to examine associations, adjusting for pregravid BMI (kg/m2), delivery mode, duration of human milk feeding, and infant sex, with q < 0.2 considered significant. RESULTS: This analysis included a total of 54 mothers (100% exclusively feeding human milk) and infants (n = 28 male; 51.9%). Total energy in human milk showed a negative association with α-diversity measures (Chao1 and Shannon). Interleukin (IL)-8 in human milk was positively associated with Chao1 and observed operational taxonomic units. At the family level, human milk glutamine and serine levels showed a negative association with the abundance of Veillonellaceae, whereas isoleucine showed a positive association with Bacteroidaceae. Human milk IL-8 and IL-6 concentrations were positively associated with Bacteroidaceae abundance. IL-8 also had a positive relationship with Bifidobacteriaceae, whereas it had a negative relationship with Streptococcacea and Clostridiaceae. Human milk IL-8 was positively associated with the phylum Bacteroidetes, and negatively associated with Proteobacteria. At the genus level, human milk IL-8 exhibited a positive relationship with Bacteroides, whereas human milk isoleucine had a negative relationship with Bacteroides and Ruminococcus. Pregravid BMI and sex effects were observed. CONCLUSIONS: IL-8 in human milk could potentially prepare the infant's immune system to respond effectively to various microorganisms, potentially promoting the growth of beneficial gut bacteria and protecting against pathogens.
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Microbioma Gastrointestinal , Leite Humano , Lactente , Feminino , Humanos , Masculino , Leite Humano/química , Microbioma Gastrointestinal/genética , Interleucina-8/análise , Interleucina-8/metabolismo , Estudos Transversais , RNA Ribossômico 16S/genética , Isoleucina/análise , Isoleucina/metabolismo , Fezes/microbiologia , Aleitamento MaternoRESUMO
Loss of ovarian function imparts increased susceptibility to obesity and metabolic disease. These effects are largely attributed to decreased estradiol (E2), but the role of increased follicle-stimulating hormone (FSH) in modulating energy balance has not been fully investigated. Previous work that blocked FSH binding to its receptor in mice suggested this hormone may play a part in modulating body weight and energy expenditure after ovariectomy (OVX). We used an alternate approach to isolate the individual and combined contributions of FSH and E2 in mediating energy imbalance and changes in tissue-level metabolic health. Female Wistar rats were ovariectomized and given the gonadotropin releasing hormone (GnRH) antagonist degarelix to suppress FSH production. E2 and FSH were then added back individually and in combination for a period of 3 wk. Energy balance, body mass composition, and transcriptomic profiles of individual tissues were obtained. In contrast to previous studies, suppression and replacement of FSH in our paradigm had no effect on body weight, body composition, food intake, or energy expenditure. We did, however, observe organ-specific effects of FSH that produced unique transcriptomic signatures of FSH in retroperitoneal white adipose tissue. These included reductions in biological processes related to lipogenesis and carbohydrate transport. In addition, rats administered FSH had reduced liver triglyceride concentration (P < 0.001), which correlated with FSH-induced changes at the transcriptomic level. Although not appearing to modulate energy balance after loss of ovarian function in rats, FSH may still impart tissue-specific effects in the liver and white adipose tissue that might affect the metabolic health of those organs.NEW & NOTEWORTHY We find no effect of follicle-stimulating hormone (FSH) on energy balance using a novel model in which rats are ovariectomized, subjected to gonadotropin-releasing hormone antagonism, and systematically given back FSH by osmotic pump. However, tissue-specific effects of FSH on adipose tissue and liver were observed in this study. These include unique transcriptomic signatures induced by the hormone and a stark reduction in hepatic triglyceride accumulation.
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Metabolismo Energético , Estradiol , Hormônio Foliculoestimulante , Ovariectomia , Ratos Wistar , Animais , Feminino , Metabolismo Energético/efeitos dos fármacos , Ratos , Hormônio Foliculoestimulante/metabolismo , Estradiol/farmacologia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Transcriptoma/efeitos dos fármacosRESUMO
OBJECTIVE: Menopause adversely impacts systemic energy metabolism and increases the risk of metabolic disease(s) including hepatic steatosis, but the mechanisms are largely unknown. Dosing female mice with vinyl cyclohexene dioxide (VCD) selectively causes follicular atresia in ovaries, leading to a murine menopause-like phenotype. METHODS: In this study, we treated female C57BL6/J mice with VCD (160 mg/kg i.p. for 20 consecutive days followed by verification of the lack of estrous cycling) to investigate changes in body composition, energy expenditure (EE), hepatic mitochondrial function, and hepatic steatosis across different dietary conditions. RESULTS: VCD treatment induced ovarian follicular loss and increased follicle-stimulating hormone (FSH) levels in female mice, mimicking a menopause-like phenotype. VCD treatment did not affect body composition, or EE in mice on a low-fat diet (LFD) or in response to a short-term (1-week) high-fat, high sucrose diet (HFHS). However, the transition to a HFHS lowered cage activity in VCD mice. A chronic HFHS diet (16 weeks) significantly increased weight gain, fat mass, and hepatic steatosis in VCD-treated mice compared to HFHS-fed controls. In the liver, VCD mice showed suppressed hepatic mitochondrial respiration on LFD, while chronic HFHS resulted in compensatory increases in hepatic mitochondrial respiration. Also, liver RNA sequencing revealed that VCD promoted global upregulation of hepatic lipid/cholesterol synthesis pathways. CONCLUSION: Our findings suggest that the VCD-induced menopause model compromises hepatic mitochondrial function and lipid/cholesterol homeostasis that sets the stage for HFHS diet-induced steatosis while also increasing susceptibility to obesity.
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Alcenos , Fígado Gorduroso , Atresia Folicular , Feminino , Camundongos , Animais , Menopausa , Ovário/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Modelos Animais de Doenças , Colesterol/metabolismo , Aumento de PesoRESUMO
BACKGROUND: Fetal growth restriction (FGR) increases risk for development of obesity and type 2 diabetes. Using a mouse model of FGR, we tested whether metabolic outcomes were exacerbated by high-fat diet challenge or associated with fecal microbial taxa. METHODS: FGR was induced by maternal calorie restriction from gestation day 9 to 19. Control and FGR offspring were weaned to control (CON) or 45% fat diet (HFD). At age 16 weeks, offspring underwent intraperitoneal glucose tolerance testing, quantitative MRI body composition assessment, and energy balance studies. Total microbial DNA was used for amplification of the V4 variable region of the 16 S rRNA gene. Multivariable associations between groups and genera abundance were assessed using MaAsLin2. RESULTS: Adult male FGR mice fed HFD gained weight faster and had impaired glucose tolerance compared to control HFD males, without differences among females. Irrespective of weaning diet, adult FGR males had depletion of Akkermansia, a mucin-residing genus known to be associated with weight gain and glucose handling. FGR females had diminished Bifidobacterium. Metabolic changes in FGR offspring were associated with persistent gut microbial changes. CONCLUSION: FGR results in persistent gut microbial dysbiosis that may be a therapeutic target to improve metabolic outcomes. IMPACT: Fetal growth restriction increases risk for metabolic syndrome later in life, especially if followed by rapid postnatal weight gain. We report that a high fat diet impacts weight and glucose handling in a mouse model of fetal growth restriction in a sexually dimorphic manner. Adult growth-restricted offspring had persistent changes in fecal microbial taxa known to be associated with weight, glucose homeostasis, and bile acid metabolism, particularly Akkermansia, Bilophilia and Bifidobacteria. The gut microbiome may represent a therapeutic target to improve long-term metabolic outcomes related to fetal growth restriction.
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Diabetes Mellitus Tipo 2 , Retardo do Crescimento Fetal , Humanos , Feminino , Adulto , Masculino , Lactente , Retardo do Crescimento Fetal/metabolismo , Dieta Hiperlipídica , Aumento de Peso , Glucose , Desenvolvimento FetalRESUMO
BACKGROUND: Infant feeding patterns have been linked with obesity risk in childhood, but associations with precise measures of body fat distribution are unclear. OBJECTIVE: We examined associations of infant feeding practices with abdominal fat and hepatic fat trajectories in childhood. METHODS: This study included 356 children in the Healthy Start Study, a prospective prebirth cohort in Colorado. Infant feeding practices were assessed by postnatal interviews and categorized as any human milk <6 mo compared with ≥6 mo; complementary foods introduced ≤4 mo compared with >4 mo; soda introduced ≤18 mo compared with >18 mo. Abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) areas and hepatic fat (%) were assessed by magnetic resonance imaging in early and middle childhood (median 5 and 9 y old, respectively). We examined associations of infant feeding with adiposity trajectories across childhood using linear mixed models. RESULTS: In the sample of children, 67% consumed human milk ≥6 mo, 75% were introduced to complementary foods at >4 mo, and 81% were introduced to soda at >18 mo. We did not find any associations between duration of any human milk consumption and childhood adiposity trajectories. Early introduction to complementary foods (≤4 mo) was associated with faster rates of change for SAT and VAT during childhood (Slope [95% CI]: 15.1 [10.7,19.4] cm2/y for SAT; 2.5 [1.9,2.9] cm2/y for VAT), compared with introduction at >4 mo (5.5 [3.0,8.0] cm2/y and 1.6 [1.3,1.9] cm2/y, respectively). Similarly, early introduction to soda (≤18 mo) was associated with faster rates of change for all 3 outcomes during childhood (Slope [95% CI]: 20.6 [15.0,26.1] cm2/y for SAT, 2.7 [2.0,3.3] cm2/y for VAT, 0.3 [0.1,0.5] %/year for hepatic fat) compared with delayed introduction (5.4 [2.8,8.0] cm2/y, 1.7 [1.3, 2.0] cm2/y, -0.1 [-0.2,0.0] %/y, respectively). CONCLUSIONS: The timing of introduction and quality of complementary foods in infancy was associated with rates of abdominal and hepatic fat accrual during childhood. Experimental studies are needed to assess underlying mechanisms.
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Adiposidade , Obesidade Infantil , Lactente , Humanos , Criança , Estudos Prospectivos , Estudos Longitudinais , Gordura Abdominal , Obesidade Infantil/epidemiologia , Obesidade Infantil/etiologia , Obesidade Infantil/patologia , Gordura Intra-Abdominal , Comportamento AlimentarRESUMO
While exercise (EX) during pregnancy is beneficial for both mother and child, little is known about the mechanisms by which maternal exercise mediates changes in utero. Six-week-old female C57BL/6 mice were divided into two groups: with (exercise, EX; N = 7) or without (sedentary, SED; N = 8) access to voluntary running wheels. EX was provided via 24 h access to wheels for 10 weeks prior to conception until late pregnancy (18.5 days post coitum). Sex-stratified placentas and fetal livers were collected. Microarray analysis of SED and EX placentas revealed that EX affected gene transcript expression of 283 and 661 transcripts in male and female placentas, respectively (±1.4-fold, p < 0.05). Gene Set Enrichment and Ingenuity Pathway Analyses of male placentas showed that EX led to inhibition of signaling pathways, biological functions, and down-regulation of transcripts related to lipid and steroid metabolism, while EX in female placentas led to activation of pathways, biological functions, and gene expression related to muscle growth, brain, vascular development, and growth factors. Overall, our results suggest that the effects of maternal EX on the placenta and presumably on the offspring are sexually dimorphic.
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Exercício Físico , Mães , Placenta , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placenta/metabolismo , Transdução de SinaisRESUMO
Men are diagnosed with type 2 diabetes at lower body mass indexes than women; the role of skeletal muscle in this sex difference is poorly understood. Type 2 diabetes impacts skeletal muscle, particularly in females who demonstrate a lower oxidative capacity compared to males. To address mechanistic differences underlying this sex disparity, we investigated skeletal muscle mitochondrial respiration in female and male rats in response to chronic high-fat, high-sugar (HFHS) diet consumption. Four-week-old Wistar Rats were fed a standard chow or HFHS diet for 14 weeks to identify sex-specific adaptations in mitochondrial respirometry and characteristics, transcriptional patterns, and protein profiles. Fat mass was greater with the HFHS diet in both sexes when controlled for body mass (p < 0.0001). Blood glucose and insulin resistance were greater in males (p = 0.01) and HFHS-fed rats (p < 0.001). HFHS-fed males had higher mitochondrial respiration compared with females (p < 0.01 sex/diet interaction). No evidence of a difference by sex or diet was found for mitochondrial synthesis, dynamics, or quality to support the mitochondrial respiration sex/diet interaction. However, transcriptomic analyses indicate sex differences in nutrient handling. Sex-specific differences occurred in PI3K/AKT signaling, PPARα/RXRα, and triacylglycerol degradation. These findings may provide insight into the clinical sex differences in body mass index threshold for diabetes development and tissue-specific progression of insulin resistance.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Ratos , Feminino , Masculino , Animais , Sacarose/metabolismo , Resistência à Insulina/fisiologia , Caracteres Sexuais , Ratos Wistar , Gorduras na Dieta/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Dieta Hiperlipídica/efeitos adversos , Músculo Esquelético/metabolismo , InsulinaRESUMO
OBJECTIVE: Growing evidence suggests that environmental heat stress negatively influences fetal growth and pregnancy outcomes. However, few studies have examined the impact of heat stress on pregnancy outcomes in low-resource settings. We combined data from a large multi-country maternal-child health registry and meteorological data to assess the impacts of heat stress. DESIGN: Retrospective cohort study. SETTING: Three sites based in south Asia as part of the Global Network for Women's and Children's Health research in India (Belagavi and Nagpur) and Pakistan (Thatta). POPULATION OR SAMPLE: Data from women enrolled between 2014 and 2020 in the Global Network's Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnancies, were used. METHODS: A total of 126 273 pregnant women were included in this analysis. Daily maximal air temperatures (Tmax ) were acquired from local meteorological records. Associations between averages of daily maximal temperatures for each trimester and main outcomes were analysed using a modified Poisson regression approach. MAIN OUTCOMES MEASURES: Incidence of stillbirth, preterm birth, low birthweight (<2500 g) or evidence of pregnancy hypertension or pre-eclampsia. RESULTS: In the overall cohort, risk of preterm birth was positively associated with greater temperature in the second trimester (relative risk [RR] 1.05, 95% CI 1.02-1.07, p = 0.0002). Among individual sites, the risk of preterm birth was greatest in Nagpur (RR 1.07, 95% CI 1.03-1.11, p = 0.0005) and associated with second-trimester temperature. The overall risk of low birthweight was associated with ambient temperature in second trimester (RR 1.02, 95% CI 1.01-1.04, p = 0.01). The risk for LBW was associated with first-trimester heat in Thatta and with second-trimester heat in Nagpur. Finally, the overall risk of gestational hypertensive disease was associated with greater temperature in the third trimester among all sites (RR 1.07, 95% CI 1.02-1.12, p = 0.005) and was particularly significant for Nagpur (RR 1.13, 95% CI 1.05-1.23, p = 0.002). These findings highlight the increased risk of detrimental obstetric and neonatal outcomes with greater temperature. CONCLUSION: In a multi-country, community-based study, greater risk of adverse outcomes was observed with increasing temperature. The study highlights the need for deeper understanding of covarying factors and intervention strategies, especially in regions where high temperatures are common.
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Pré-Eclâmpsia , Nascimento Prematuro , Gravidez , Feminino , Recém-Nascido , Humanos , Criança , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Temperatura , Peso ao Nascer , Saúde do Lactente , Saúde da Criança , Estudos Prospectivos , Estudos Retrospectivos , Saúde da Mulher , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/etiologia , Sistema de RegistrosRESUMO
BACKGROUND: Evidence indicates a link between the pathogenesis of type 1 diabetes (T1D) and the gut microbiome. However, the regulation of microbial metabolic pathways and the associations of bacterial species with dietary factors in T1D are largely unknown. We investigated whether microbial metagenomic signatures in adolescents with T1D are associated with clinical/dietary factors. METHODS: Adolescents with T1D (case) and healthy adolescents (control) were recruited, and microbiome profiling in participants' stool samples was performed using shotgun metagenomic sequencing. The bioBakery3 pipeline (Kneaddata, Metaphlan 4 and HUMAnN) was used to assign taxonomy and functional annotations. Clinical (HbA1c) and dietary information (3-day food record) were collected for conducting association analysis using Spearman's correlation. FINDINGS: Adolescents with T1D exhibited modest changes in taxonomic composition of gut microbiome. Nineteen microbial metabolic pathways were altered in T1D, including downregulation of biosynthesis of vitamins (B2/flavin, B7/biotin and B9/folate), enzyme cofactors (NAD+ and s-adenosyl methionine) and amino acids (aspartate, asparagine and lysine) with an upregulation in the fermentation pathways. Furthermore, bacterial species associated with dietary and clinical factors differed between healthy adolescents and adolescents with T1D. Supervised models modeling identified taxa predictive of T1D status, and the top features included Coprococcus and Streptococcus. INTERPRETATION: Our study provides new insight into the alteration of microbial and metabolic signatures in adolescents with T1D, suggesting that microbial biosynthesis of vitamins, enzyme cofactors and amino acids may be potentially altered in T1D. FUNDING: Research grants from NIH/NCCIH: R01AT010247 and USDA/NIFA: 2019-67017-29253; and Larry & Gail Miller Family Foundation Assistantship.
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Diabetes Mellitus Tipo 1 , Microbiota , Humanos , Adolescente , Fezes/microbiologia , Bactérias , Vitaminas/metabolismo , Aminoácidos/metabolismoRESUMO
Compared with males, premenopausal women and female rodents are protected against hepatic steatosis and present with higher functioning mitochondria (greater hepatic mitochondrial respiration and reduced H2O2 emission). Despite evidence that estrogen action mediates female protection against steatosis, mechanisms remain unknown. Here we validated a mouse model with inducible reduction of liver estrogen receptor alpha (ERα) (LERKO) via adeno-associated virus (AAV) Cre. We phenotyped the liver health and mitochondrial function of LERKO mice (n = 10-12 per group) on a short-term high-fat diet (HFD), and then tested whether timing of LERKO induction at 2 timepoints (sexually immature: 4 weeks old [n = 11 per group] vs sexually mature: 8-10 weeks old [n = 8 per group]) would impact HFD-induced outcomes. We opted for an inducible LERKO model due to known estrogen-mediated developmental programming, and we reported both receptor and tissue specificity with our model. Control mice were ERαfl/fl receiving AAV with green fluorescent protein (GFP) only. Results show that there were no differences in body weight/composition or hepatic steatosis in LERKO mice with either short-term (4-week) or chronic (8-week) high-fat feeding. Similarly, LERKO genotype nor timing of LERKO induction (pre vs post sexual maturity) did not alter hepatic mitochondrial O2 and H2O2 flux, coupling, or OXPHOS protein. Transcriptomic analysis showed that hepatic gene expression in LERKO was significantly influenced by developmental stage. Together, these studies suggest that hepatic ERα is not required in female protection against HFD-induced hepatic steatosis nor does it mediate sexual dimorphism in liver mitochondria function.
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OBJECTIVES: Maternal prepregnancy BMI (ppBMI) and an infant's rapid weight gain (RWG) are each associated with increased risk for childhood obesity. We hypothesized that ppBMI and RWG interact to further raise childhood obesity risk. METHODS: Mother-infant dyads (n = 414) from the Healthy Start Study, an observational prebirth cohort, were included. RWG was defined as a weight-for-age z score increase of ≥0.67 from birth to 3 to 7 months. Body composition was measured by air displacement plethysmography at age 4 to 7 years. General linear regression models were fit to characterize associations between ppBMI, RWG, and their interaction with the outcomes of childhood BMI-for-age z score and percent fat mass (%FM). RESULTS: A total of 18.6% (n = 77) of offspring experienced RWG. Maternal ppBMI and RWG were both positively associated with offspring BMI z score and %FM. RWG amplified the association between ppBMI and BMI z score, especially among females. Females exposed to maternal obesity and RWG had an average BMI at the 94th percentile (1.50 increase in childhood BMI z score) compared with those exposed to normal ppBMI and no RWG (average childhood BMI at the 51st percentile). RWG had a weaker effect on the association between ppBMI and %FM. Adjustment for breastfeeding status or childhood daily caloric intake did not significantly alter findings. CONCLUSIONS: Rapid infant weight gain interacts with maternal ppBMI to jointly exacerbate risk of childhood obesity. Pediatric providers should monitor infants for RWG, especially in the context of maternal obesity, to reduce future risk of obesity.
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Obesidade Materna , Obesidade Infantil , Lactente , Criança , Humanos , Feminino , Gravidez , Pré-Escolar , Recém-Nascido , Índice de Massa Corporal , Obesidade Infantil/epidemiologia , Obesidade Infantil/etiologia , Obesidade Materna/epidemiologia , Aumento de Peso , Mães , Composição Corporal , Peso ao NascerRESUMO
Activation of thermogenic adipose tissue depots has been linked to improved metabolism and weight loss. To study the molecular regulation of adipocyte thermogenesis, we performed RNA-Seq on brown adipose tissue (BAT), gonadal white adipose tissue (gWAT), and inguinal white adipose tissue (iWAT) from mice treated with ß3-adrenoreceptor agonist CL316,243 (CL). Our analysis revealed diverse transcriptional profile and identified pathways in response to CL treatment. Differentially expressed genes (DEGs) in iWATCL were associated with the upregulation of pathways involved in cellular immune responses and with the upregulation of the browning program. We identified 39 DEGs in beige adipose which included certain heat shock proteins (Hspa1a and Hspa1b), and others suggesting potential associations with browning. Our results highlight transcriptional heterogeneity across adipose tissues and reveal genes specifically regulated in beige adipose, potentially aiding in identifying novel browning pathways.
Assuntos
Tecido Adiposo Branco , Transcriptoma , Camundongos , Animais , Tecido Adiposo Branco/metabolismo , Tecido Adiposo , Tecido Adiposo Marrom/metabolismo , Adipócitos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/metabolismo , Obesidade/metabolismo , Termogênese/genética , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Overnutrition in utero may increase offspring risk of nonalcoholic fatty liver disease (NAFLD), but the specific contribution of maternal diet quality during pregnancy to this association remains understudied in humans. OBJECTIVES: This study aimed to examine the associations of maternal diet quality during pregnancy with offspring hepatic fat in early childhood (median: 5 y old, range: 4-8 y old). METHODS: Data were from 278 mother-child pairs in the longitudinal, Colorado-based Healthy Start Study. Multiple 24-h recalls were collected from mothers during pregnancy on a monthly basis (median: 3 recalls, range: 1-8 recalls starting after enrollment), and used to estimate maternal usual nutrient intakes and dietary pattern scores [Healthy Eating Index-2010 (HEI-2010), Dietary Inflammatory Index (DII), and Relative Mediterranean Diet Score (rMED)]. Offspring hepatic fat was measured in early childhood by MRI. Associations of maternal dietary predictors during pregnancy with offspring log-transformed hepatic fat were assessed using linear regression models adjusted for offspring demographics, maternal/perinatal confounders, and maternal total energy intake. RESULTS: Higher maternal fiber intake and rMED scores during pregnancy were associated with lower offspring hepatic fat in early childhood in fully adjusted models [Back-transformed ß (95% CI): 0.82 (0.72, 0.94) per 5 g/1000 kcal fiber; 0.93 (0.88, 0.99) per 1 SD for rMED]. In contrast, higher maternal total sugar and added sugar intakes, and DII scores were associated with higher offspring hepatic fat [Back-transformed ß (95% CI): 1.18 (1.05, 1.32) per 5% kcal/d added sugar; 1.08 (0.99, 1.18) per 1 SD for DII]. Analyses of dietary pattern subcomponents also revealed that lower maternal intakes of green vegetables and legumes and higher intake of "empty calories" were associated with higher offspring hepatic fat in early childhood. CONCLUSIONS: Poorer maternal diet quality during pregnancy was associated with greater offspring susceptibility to hepatic fat in early childhood. Our findings provide insights into potential perinatal targets for the primordial prevention of pediatric NAFLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Gravidez , Feminino , Humanos , Pré-Escolar , Criança , Fenômenos Fisiológicos da Nutrição Materna , Dieta , Ingestão de Energia , AçúcaresRESUMO
Rapid changes in the global climate are deepening existing health disparities from resource scarcity and malnutrition. Rising ambient temperatures represent an imminent risk to pregnant women and infants. Both maternal malnutrition and heat stress during pregnancy contribute to poor fetal growth, the leading cause of diminished child development in low-resource settings. However, studies explicitly examining interactions between these two important environmental factors are lacking. We leveraged maternal and neonatal anthropometry data from a randomized controlled trial focused on improving preconception maternal nutrition (Women First Preconception Nutrition trial) conducted in Thatta, Pakistan, where both nutritional deficits and heat stress are prevalent. Multiple linear regression of ambient temperature and neonatal anthropometry at birth (n = 459) showed a negative association between daily maximal temperatures in the first trimester and Z-scores of birth length and head circumference. Placental mRNA-sequencing and protein analysis showed transcriptomic changes in protein translation, ribosomal proteins, and mTORC1 signaling components in term placenta exposed to excessive heat in the first trimester. Targeted metabolomic analysis indicated ambient temperature associated alterations in maternal circulation with decreases in choline concentrations. Notably, negative impacts of heat on birth length were in part mitigated in women randomized to comprehensive maternal nutritional supplementation before pregnancy suggesting potential interactions between heat stress and nutritional status of the mother. Collectively, the findings bridge critical gaps in our current understanding of how maternal nutrition may provide resilience against adverse effects of heat stress in pregnancy.
RESUMO
Menopause adversely impacts systemic energy metabolism and increases the risk of metabolic disease(s) including hepatic steatosis, but the mechanisms are largely unknown. Dosing female mice with vinyl cyclohexene dioxide (VCD) selectively causes follicular atresia in ovaries, leading to a murine menopause-like phenotype. In this study, we treated female C57BL6/J mice with VCD (160mg/kg i.p. for 20 consecutive days followed by verification of the lack of estrous cycling) to investigate changes in body composition, energy expenditure (EE), hepatic mitochondrial function, and hepatic steatosis across different dietary conditions. VCD treatment induced ovarian follicular loss and increased follicle-stimulating hormone (FSH) levels in female mice, mimicking a menopause-like phenotype. VCD treatment did not affect body composition, or EE in mice on a low-fat diet or in response to a short-term (1-week) high-fat, high sucrose diet (HFHS). However, the transition to a HFHS lowered cage activity in VCD mice. A chronic HFHS diet (16 weeks) significantly increased weight gain, fat mass, and hepatic steatosis in VCD-treated mice compared to HFHS-fed controls. In the liver, VCD mice showed suppressed hepatic mitochondrial respiration on LFD, while chronic HFHS diet resulted in compensatory increases in hepatic mitochondrial respiration. Also, liver RNA sequencing revealed that VCD promoted global upregulation of hepatic lipid/cholesterol synthesis pathways. Our findings suggest that the VCD- induced menopause model compromises hepatic mitochondrial function and lipid/cholesterol homeostasis that sets the stage for HFHS diet-induced steatosis while also increasing susceptibility to obesity.